1,5 Benzodiazepine derivatives

ABSTRACT

1,5-Benzodiazepine derivatives represented by formula (I), salts thereof, and medicines containing the same as the active ingredient:                    
     The compounds exhibit excellent gastrin and/or CCK-B receptor antagonism and are useful as remedies for gastric ulcer and gastrointestinal movement disorder.

This application is a national stage entry under 35 U.S.C. 371 ofPCT/JP97/04534 filed Dec. 10, 1997.

TECHNICAL FIELD

The present invention relates to 1,5-benzodiazepine derivatives, whichare important in the medical field. More specifically, the presentinvention relates to novel 1,5-benzodiazepine derivatives which havegastrin and/or CCK-B (cholecystokinin-B) receptor antagonism, and topreventive and therapeutic remedies for disorders in which the receptorsparticipate.

BACKGROUND ART

Cholecystokinin (CCK) is a gastrointestinal hormone which is produced byand released from duodenal and jejunal mucous membranes, and is known tohave actions such as secretion of pancreatic juice, gallbladderconstriction, and stimulation of insulin secretion. CCK is also known tobe present at high concentration in the cerebral cortex, hypothalamus,and hippocampus. CCK is also known to exhibit various actions, includinginhibition of eating and hunger, augmentation of memory, and generationof anxiety. Meanwhile, gastrin is a gastrointestinal hormone which isproduced by and released from G-cells distributed in the pylorus.Gastrin is also known to exhibit actions such as secretion of gastricacid and constriction of the pylorus and gallbladder. CCK and gastrin,having the same five amino acids in their C-terminals, exert theaforementioned actions via receptors. The receptors of CCK areclassified into CCK-A receptors, which are of the peripheral-type andare distributed in the pancreas, the gallbladder, and the intestines;and CCK-B receptors, which are of the central-type and are distributedwithin the brain. Since gastrin receptors and CCK-B receptors showsimilar properties in receptor-binding experiments, and thus are provento have high homology, they are often called CCK-B/gastrin receptors.Compounds having antagonism to these receptors, i.e., gastrin or CCK-Breceptor, are expected to be useful for prevention and treatment of thefollowing diseases and disorders: gastric ulcer, duodenal ulcer,gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome,vacuolating G-cell hyperplasia, basal-mucous-membrane hyperplasia,inflammation of the gallbladder, attack of biliary colic, motordisorders of alimentary canal, irritable bowel syndrome, certain typesof tumors, eating disorders, anxiety, panic disorder, depression,schizophrenia, Parkinson's disease, tardive dyskinesia, Gilles de laTourette syndrome, drug dependence, and drug-withdrawal symptoms.Moreover, the compounds are expected to induce pain relief or to augmentthe pain-relieving effect of opioid analgesics (Folia PharmacologicaJaponica, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18.919-931 (1993), American Journal of Physiology, Vol. 269, G628-G646(1995), American Journal of Physiology, Vol. 259, G184-G190 (1990),European Journal of Pharmacology, 261, 257-263 (1994), Trends inPharmacological Science, Vol. 15, 65-66 (1994)).

Proglumide, which is a drug having gastrin receptor antagonism, hasconventionally been known as a remedy for gastric ulcer and gastritis.However, proglumide has a very weak affinity with gastrin or CCK-Breceptors, and has a low curative effect. It is described that some1,4-benzodiazepine derivatives—such as L-364,718 (Dibazepaido, JapanesePatent Application Laid-Open (kokai) No. 63666/1986) and L-365,260(Japanese Patent Application Laid-Open (kokai) No. 238069/1988)—exhibitCCK-A receptor antagonism or CCK-B receptor antagonism. It is also knownthat compounds having strong CCK-B receptor antagonism suppresssecretion of gastric acid stimulated by pentagastrin (WO 94/438 and WO95/18110). However, these compounds do not provide satisfactory effectswhen administered in vivo. Drugs which exhibit gastrin or CCK-B receptorantagonism and are clinically useful have not yet been provided.

Compounds that can be strongly bound to gastrin or cholecystokininreceptors are expected to be useful as remedies and for prevention ofdiseases associated with respective receptors and found in thealimentary canal and the central nervous system.

DISCLOSURE OF THE INVENTION

In view of the foregoing, in order to solve the above-mentionedproblems, the present inventors have conducted earnest studies, and havefound that some 1,5-benzodiazepine derivatives exhibit gastrin and/orCCK-B receptor antagonism and strong effect in suppressing the secretionof gastric acid, and that the derivatives are useful as medicines,leading to completion of the invention.

Accordingly, the present invention provides a 1,5-benzodiazepinederivative represented by the following formula (I) and salts thereof:

[wherein

R₁ represents a hydrogen atom, a lower alkyl group, a lower alkoxylgroup, or a halogen atom;

each of R₂ and R₃, which may be the same or different, represents ahydrogen atom, a lower alkenyl group, a lower alkyl group which may besubstituted by a halogen atom, a lower alkylsulfonyl group, a mono- ordi-lower alkoxyalkyl group, a phenyl group which may have a substituent,a group represented by —CH(R₆)R₇ (wherein R₆ represents a lower alkylgroup, a lower alkoxyl group, a mono- or di-lower alkoxyalkyl group, asaturated or unsaturated hydrocarbon group having a C7-C10 condensedring, or a phenyl or heterocyclic group which may have a substituent;and R₇ represents a hydrogen atom or a lower alkyl group), or a grouprepresented by —CO—R₈ (wherein R₈ represents a lower alkyl group whichmay be substituted by a halogen atom; a lower alkenyl group; a loweralkoxyl group; a mono- or di-lower alkoxyalkyl group; an adamantylgroup; a hydroxyl group; a benzyloxy group; a phenyl or heterocyclicgroup which may have a substituent; or a group represented by —N(R₉)R₁₀(wherein R₉ and R₁₀ may be the same or different, and each represents ahydrogen atom, a lower alkyl group, a hydroxyalkyl group, a mono- ordi-lower alkylaminoalkyl group, a phenyl group, or a heterocyclic groupwhich may have a substituent));

each of R₄ and R₅, which may be identical to or different from eachother, represents a hydrogen atom, a lower alkyl group which may besubstituted by a halogen atom, a lower alkoxyl group, a halogen atom, ahydroxyalkyl group, an amino group, a nitro group, a mono- or di-loweralkylamino group, a lower alkylsulfonylaminocarbonyl group, ahydroxyaminocarbonyl group, a benzyloxyaminocarbonyl group, a tetrazolylgroup, a 4-oxoxadiazolinyl group, a group represented by the followingformula:

(wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R¹¹ represents ahydrogen atom, a lower alkyl group or a benzyl group);

Ar represents an aromatic hydrocarbon or an aromatic heterocyclic ring;and

n represents an integer between 0 and 2 inclusive].

The present invention also provides a medicine containing theabove-described compound (I) as an active ingredient.

The present invention also provides a pharmaceutical compositioncontaining the above-described compound (I) and a pharmaceuticallyacceptable carrier.

The present invention also provides use of the above-described compound(I) as a medicine.

The present invention also provides a method for prevention andtreatment of a disease in which a gastrin receptor and/orcholecystokinin (CCK)-B receptor participates, which comprisesadministration of an effective amount of the above-described compound(I) to mammals, including humans.

BEST MODE FOR CARRYING OUT THE INVENTION

As used herein, “lower” refers to a straight, branched, or cyclic carbonchain having 1-8 carbon atoms, and “lower cyclic” refers to C3-C8monocyclic.

Therefore, examples of a “lower alkyl group” include methyl, ethyl,propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, cyclopropylmethyl, 1-methylcyclopropyl, 2-methylcyclopropyl,pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl,1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl,1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl,cyclobutylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl,(1-methylcyclopropyl)methyl, (2-methylpropyl)methyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl,2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, cyclohexyl, heptyl, 1-methylhexyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl,2-ethylpentyl, 3-ethylpentyl, 1-propylbutyl, cycloheptyl,1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl,5-methylheptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 1-propylpentyl, 2-propylpentyl,3,3,4-trimethylpentyl, 3,4,4-trimethylpentyl, 1,1,2,2-tetramethylbutyl,2,2,3,3-tetramethylbutyl, 1,1,3,3-tetramethylbutyl, and cyclooctyl.

As used herein, a “lower alkoxyl group” refers to a straight, branched,or cyclic alkoxyl group having 1-8 carbon atoms, and examples thereofinclude methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, cyclopropylmethoxy,1-methylcyclopropoxy, 2-methylcyclopropoxy, pentyloxy, 1-methylbutoxy,2-methylbutoxy, isopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy,neopentyloxy, 1-ethylpropoxy, cyclopentyloxy, 1-methylcyclobutoxy,2-methylcyclobutoxy, 3-methylcyclobutoxy, cyclobutylmethoxy,1-cyclopropylethoxy, 2-cyclopropylethoxy, (1-methylcyclopropyl)methoxy,(2-methylpropyl)methoxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy,3-methylpentyloxy, isohexyloxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-methyl-1-ethylpropoxy, 1-ethyl-2-methylpropoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, cyclohexyloxy,heptyloxy, 1-methylhexyloxy, 2-methylhexyloxy, 2-methylhexyloxy,4-methylhexyloxy, 5-methylhexyloxy, 1-ethylpentyloxy, 2-ethylpentyloxy,3-ethylpentyloxy, 1-propylbutyloxy, cycloheptyloxy, 1-methylheptyloxy,2-methylheptyloxy, 3-methylheptyloxy, 4-methylheptyloxy,5-methylheptyloxy, 6-methylheptyloxy, 1-ethylhexyloxy, 2-ethylhexyloxy,3-ethylhexyloxy, 4-ethylhexyloxy, 1-propylpentyloxy, 2-propylpentyloxy,3,3,4-trimethylpentyloxy, 3,4,4-trimethylpentyloxy,1,1,2,2-tetramethylbutyloxy, 2,2,3,3-tetramethylbutyloxy,1,1,3,3-tetramethylbutyloxy, and cyclooctyloxy.

As used herein, a “halogen atom” refers to fluorine, chlorine, bromine,or iodine.

As used herein, a “lower alkenyl group” refers to a straight, branched,or cyclic carbon chain having one double bond and 2-8 carbon atoms.

Therefore, examples of a “lower alkenyl group” include vinyl,1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-ethyl-1-propenyl, 1,2-dimethyl-1-propenyl, 1-ethyl-2-propenyl,1,2-dimethyl-2-propenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl,6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl,6-octenyl, 7-octenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl, 1,2-dimethyl-1-butenyl,1,3-dimethyl-1-butenyl, 2,3-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,3-dimethyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-3-butenyl, 2,3-dimethyl-3-butenyl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 2-cyclohexen-1-yl, 2-cyclohepten-1-yl,2-cycloocten-1-yl, and 2-cyclopenten-1-yl.

As used herein, a “lower alkyl group which may be substituted by ahalogen atom” refers to a lower alkyl group which has no halogen atombonded thereto or which has one to three halogen atoms bonded thereto. A“halogen atom” and a “lower alkyl atom” refers to the above-defined“halogen atom” and “lower alkyl atom,” respectively

A “lower alkylsulfonyl group” refers to a group in which a lower alkylgroup is bonded to a sulfonyl group. A “lower alkylsulfonylaminocarbonylgroup” refers to an aminocarbonyl group to which a “lower alkylsulfonylgroup” mentioned above is bonded. A “mono- or di-lower alkoxyalkylgroup” refers to a lower alkyl group substituted by one or two “loweralkoxy groups” described above. Therefore, examples of a “mono- ordi-lower alkoxyalkyl group” include methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, cyclopropoxymethyl, butoxymethyl,isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, cyclobutoxymethyl,cyclopropylmethoxymethyl, 1-methylcyclopropoxymethyl,2-methylcyclopropoxymethyl, pentyloxymethyl, 1-methylbutoxymethyl,2-methylbutoxymethyl, isopentyloxymethyl, tert-pentyloxymethyl,1,2-dimethylpropoxymethyl, neopentyloxymethyl, 1-ethylpropoxymethyl,cyclopentyloxymethyl, 1-methylcyclobutoxymethyl,2-methylcyclobutoxymethyl, 3-methylcyclobutoxymethyl,cyclobutylmethoxymethyl, 1-cyclopropylethoxymethyl,2-cyclopropylethoxymethyl, (1-methylcyclopropyl)methoxymethyl,(2-methylpropyl)methoxymethyl, hexyloxymethyl, 1-methylpentyloxymethyl,2-methylpentyloxymethyl, 3-methylpentyloxymethyl, isohexyloxymethyl,1-ethylbutoxymethyl, 2-ethylbutoxymethyl, 1,1-dimethylbutoxymethyl,1,2-dimethylbutoxymethyl, 1,3-diethylbutoxymethyl,2,2-dimethylbutoxymethyl, 2,3-dimethylbutoxymethyl,3,3-dimethylbutoxymethyl, 1-methyl-1-ethylpropoxymethyl,1-ethyl-2-methylpropoxymethyl, 1,1,2-trimethylpropoxymethyl,1,2,2-trimethylpropoxymethyl, cyclohexyloxymethyl, dimethoxymethyl,diethoxymethyl, dipropoxymethyl, diisopropoxymethyl,dicyclopropoxymethyl, dibutoxymethyl, diisobutoxymethyl,di-sec-butoxymethyl, di-tert-butoxymethyl, dicyclobutoxymethyl,di(cyclopropylmethoxy)methyl, di(1-methylcyclopropoxy)methyl,di(2-methylcyclopropoxy)methyl, dipentyloxymethyl,di(1-methylbutoxy)methyl, di(2-methylbutoxy)methyl,diisopentyloxymethyl, di-tert-pentyloxymethyl,di(1,2-dimethylpropoxy)methyl, dineopentyloxymethyl,di(1-ethylpropoxy)methyl, dicyclopentyloxymethyl,di(1-methylcyclobutoxy)methyl, di(2-methylcyclobutoxy)methyl,di(3-methylcyclobutoxy)methyl, di(cyclobutylmethoxy)methyl,di(1-cyclopropylethoxy)methyl, di(2-cyclopropylethoxy)methyl,di[(1-methylcyclopropyl)methoxy]methyl,di[(2-methylpropyl)methoxy]methyl, dihexyloxymethyl,1-methylpentyloxymethyl, 2-methylpentyloxymethyl,di(3-methylpentyloxy)methyl, diisohexyloxymethyl,di(1-ethylbutoxy)methyl, di(2-ethylbutoxy)methyl,di(1,1-dimethylbutoxy)methyl, di(1,2-dimethylbutoxy)methyl,di(1,3-dimethylbutoxy)methyl, di(2,2-dimethylbutoxy)methyl,di(2,3-dimethylbutoxy)methyl, di(3,3-dimethylbutoxy)methyl,di(1-methyl-1-ethylpropoxy)methyl, di(1-ethyl-2-methylpropoxy)methyl,di(1,1,2-trimethylpropoxy)methyl, di(1,2,2-trimethylpropoxy)methyl,dicyclohexyloxymethyl, methoxyethoxymethyl, methoxypropoxymethyl,methoxyisopropoxymethyl, methoxycyclopropoxymethyl, methoxybutoxymethyl,methoxyisobutoxymethyl, methoxy-sec-butoxymethyl,methoxy-tert-butoxymethyl, ethoxypropoxymethyl, ethoxyisopropoxymethyl,ethoxycyclopropoxymethyl, ethoxybutoxymethyl, ethoxyisobutoxymethyl,ethoxy-sec-butoxymethyl, ethoxy-tert-butoxymethyl,propoxyisopropoxymethyl, propoxycyclopropoxymethyl, propoxybutoxymethyl,propoxyisobutoxymethyl, propoxy-sec-butoxymethyl,propoxy-tert-butoxymethyl, isopropoxycyclopropoxymethyl,isopropoxybutoxymethyl, isopropoxyisobutoxymethyl,isopropoxy-sec-butoxymethyl, isopropoxy-tert-butoxymethyl,cyclopropoxybutoxymethyl, cyclopropoxyisobutoxymethyl,cyclopropoxy-sec-butoxymethyl, cyclopropoxy-tert-butoxymethyl,butoxy-sec-butoxymethyl, butoxy-tert-butoxymethyl,isobutoxy-sec-butoxymethyl, isobutoxy-tert-butoxymethyl,sec-butoxy-tert-butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl,isopropoxyethyl, cyclopropoxyethyl, butoxyethyl, isobutoxyethyl,sec-butoxyethyl, tert-butoxyethyl, cyclobutoxyethyl,cyclopropylmethoxyethyl, 1-methylcyclopropoxyethyl,2-methylcyclopropoxyethyl, pentyloxyethyl, 1-methylbutoxyethyl,2-methylbutoxyethyl, isopentyloxyethyl, tert-pentyloxyethyl,1,2-dimethylpropoxyethyl, neopentyloxyethyl, 1-ethylpropoxyethyl,cyclopentyloxyethyl, 1-methylcyclobutoxyethyl, 2-methylcyclobutoxyethyl,3-methylcyclobutoxyethyl, cyclobutylmethoxyethyl,1-cyclopropylethoxyethyl, 2-cyclopropylethoxyethyl,(1-methylcyclopropyl)methoxyethyl, (2-methylpropyl)methoxyethyl,hexyloxyethyl, 1-methylpentyloxyethyl, 2-methylpentyloxyethyl,3-methylpentyloxyethyl, isohexyloxyethyl, 1-ethylbutoxyethyl,2-ethylbutoxyethyl, 1,1-dimethylbutoxyethyl, 1,2-dimethylbutoxyethyl,1,3-dimethylbutoxyethyl, 2,2-dimethylbutoxyethyl,2,3-dimethylbutoxyethyl, 3,3-dimethylbutoxyethyl,1-methyl-1-ethylpropoxyethyl, 1-ethyl-2-methylpropoxyethyl,1,1,2-trimethylpropoxyethyl, 1,2,2-trimethylpropoxyethyl,cyclohexyloxyethyl, dimethoxyethyl, diethoxyethyl, dipropoxyethyl,diisopropoxyethyl, dicyclopropoxyethyl, dibutoxyethyl, diisobutoxyethyl,di-sec-butoxyethyl, di-tert-butoxyethyl, dicyclobutoxyethyl,di(cyclopropylmethoxy)ethyl, di(1-methylcyclopropoxy)ethyl,di(2-methylcyclopropoxy)ethyl, dipentyloxyethyl,di(1-methylbutoxy)ethyl, di(2-methylbutoxy)ethyl, diisopentyloxyethyl,di-tert-pentyloxyethyl, di(1,2-dimethylpropoxy)ethyl,dineopentyloxyethyl, di(1-ethylpropoxy)ethyl, dicyclopentyloxyethyl,di(1-methylcyclobutoxy)ethyl, di(2-methylcyclobutoxy)ethyl,di(3-methylcyclobutoxy)ethyl, di(cyclobutylmethoxy)ethyl,di(1-cyclopropylethoxy)ethyl, di(2-cyclopropylethoxy)ethyl,di[(1-methylcyclopropyl)methoxylethyl, di[(2-methylpropyl)methoxy]ethyl,dihexyloxyethyl, 1-methylpentyloxyethyl, 2-methylpentyloxyethyl,di(3-methylpentyloxy)ethyl, diisohexyloxyethyl, di(1-ethylbutoxy)ethyl,di(2-ethylbutoxy)ethyl, di(1,1-dimethylbutoxy)ethyl,di(1,2-dimethylbutoxy)ethyl, di(1,3-dimethylbutoxy)ethyl,di(2,2-dimethylbutoxy)ethyl, di(2,3-dimethylbutoxy)ethyl,di(3,3-dimethylbutoxy)ethyl, di(1-methyl-1-ethylpropoxy)ethyl,di(1-ethyl-2-methylpropoxy)ethyl, di(1,1,2-trimethylpropoxy)ethyl,di(1,2,2-trimethylpropoxy)ethyl, dicyclohexyloxyethyl,methoxyethoxyethyl, methoxypropoxyethyl, methoxyisopropoxyethyl,methoxycyclopropoxyethyl, methoxybutoxyethyl, methoxyisobutoxyethyl,methoxy-sec-butoxyethyl, methoxy-tert-butoxyethyl,methoxypentyloxyethyl, methoxyhexyloxyethyl, ethoxypropoxyethyl,ethoxyisopropoxyethyl, ethoxycyclopropoxyethyl, ethoxybutoxyethyl,ethoxyisobutoxyethyl, ethoxy-sec-butoxyethyl, ethoxy-tert-butoxyethyl,ethoxypentyloxyethyl, ethoxyhexyloxyethyl, propoxyisopropoxyethyl,propoxycyclopropoxyethyl, propoxybutoxyethyl, propoxyisobutoxyethyl,propoxy-sec-butoxyethyl, propoxy-tert-butoxyethyl,propoxypentyloxyethyl, propoxyhexyloxyethyl,isopropoxycyclopropoxyethyl, isopropoxybutoxyethyl,isopropoxyisobutoxyethyl, isopropoxy-sec-butoxyethyl,isopropoxy-tert-butoxyethyl, isopropoxypentyloxyethyl,isopropoxyhexyloxyethyl, cyclopropoxybutoxyethyl,cyclopropoxyisobutoxyethyl, cyclopropoxy-sec-butoxyethyl,cyclopropoxy-tert-butoxyethyl, cyclopropoxypentyloxyethyl,cyclopropoxyhexyloxyethyl, butoxy-sec-butoxyethyl,butoxy-tert-butoxyethyl, butoxypentyloxyethyl, butoxyhexyloxyethyl,isobutoxy-sec-butoxyethyl, isobutoxy-tert-butoxyethyl,isobutoxypentyloxyethyl, isobutoxyhexyloxyethyl, andsec-butoxy-tert-butoxyethyl.

As used herein, a “phenyl group which may have a substituent” refers toa phenyl group which has no substituent or a phenyl group which has oneor two substituents. A “heterocyclic group which may have a substituent”refers to a heterocyclic group which has no substituent, or a 5- or6-membered heterocyclic group which has one or two substituents. As usedherein, a “substituent” represents the above-mentioned “lower alkylgroup,” the above-mentioned “lower alkoxyl group,” the above-mentioned“halogen atom,” an amino group, or a nitro group. Examples of a“heterocyclic group” include pyridyl, piperidyl, pyrrolidinyl, furyl, orthienyl.

Examples of a “saturated or unsaturated hydrocarbon having a C7-C10condensed ring” include bicyclic or tricyclic hydrocarbons, and specificexamples thereof include adamantyl, bicyclo[3.1.1]heptanyl,bicyclo[3.1.1]heptenyl, 6,6-dimethyl-bicyclo[3.1.1]heptan-2-yl, or6,6-dimethyl-bicyclo[3.1.1]hepta-2-en-2-yl.

As used herein, a “hydroxyalkyl group” refers to any of theabove-described lower alkyl groups substituted by one hydroxy group.

As used herein, a “mono- or di-lower alkylamino group” refers to anamino group substituted by one or two lower alkyl groups, and specificexamples thereof include methylamino, ethylamino, propylamino,isopropylamino, cyclopropylamino, butylamino, isobutylamino,sec-butylamino, tert-butylamino, cyclobutylamino,cyclopropylmethylamino, 1-methylcyclopropylamino,2-methylcyclopropylamino, pentylamino, 1-methylbutylamino,2-methylbutylamino, isopentylamino, tert-pentylamino,1,2-dimethylpropylamino, neopentylamino, 1-ethylpropylamino,cyclopentylamino, 1-methylcyclobutylamino, 2-methylcyclobutylamino,3-methylcyclobutylamino, cyclobutylmethylamino, 1-cyclopropylethylamino,2-cyclopropylethylamino, (1-methylcyclopropyl)methylamino,(2-methylpropyl)methylamino, hexylamino, 1-methylpentylamino,2-methylpentylamino, 3-methylpentylamino, isohexylamino,1-ethylbutylamino, 2-ethylbutylamino, 1,1-dimethylbutylamino,1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,2-dimethylbutylamino,2,3-dimethylbutylamino, 3,3-dimethylbutylamino,1-methyl-1-ethylpropylamino, 1-ethyl-2-methylpropylamino,1,1,2-trimethylpropylamino, 1,2,2-trimethylpropylamino, cyclohexylamino,dimethylamino, diethylamino, dipropylamino, diisopropylamino,dicyclopropylamino, dibutylamino, diisobutylamino, di-sec-butylamino,di-tert-butylamino, dicyclobutylamino, di(cyclopropylmethyl)amino,di(1-methylcyclopropyl)amino, di(2-methylcyclopropyl)amino,dipentylamino, di(1-methylbutyl)amino, di(2-methylbutyl)amino,diisopentylamino, di-tert-pentylamino, di(1,2-dimethylpropyl)amino,dineopentylamino, di(1-ethylpropyl)amino, dicyclopentylamino,di(1-methylcyclobutyl)amino, di(2-methylcyclobutyl)amino,di(3-methylcyclobutyl)amino, di(cyclobutylmethyl)amino,di(1-cyclopropylethyl)amino, di(2-cyclopropylethyl)amino,di(1-methylcyclopropyl)methyl]amino, di[(2-methylpropyl)methyl]amino,dihexylamino, di(1-methylpentyl)amino, di(2-methylpentyl)amino,di(3-methylpentyl)amino, diisohexylamino, di(1-ethylbutyl)amino,di(2-ethylbutyl)amino, di(1,1-dimethylbutyl)amino,di(1,2-dimethylbutyl)amino, di(1,3-dimethylbutyl)amino,di(2,2-dimethylbutyl)amino, di(2,3-dimethylbutyl)amino,di(3,3-dimethylbutyl)amino, di(1-methyl-1-ethylpropyl)amino,di(1-ethyl-2-methylpropyl)amino, di(1,1,2-trimethylpropyl)amino,di(1,2,2-trimethylpropyl)amino, dicyclohexylamino, methylethylamino,methylpropylamino, methylisopropylamino, methylcyclopropylamino,methylbutylamino, methylisobutylamino, methyl-sec-butylamino,methyl-tert-butylamino, methylpentylamino, methylhexylamino,ethylpropylamino, ethylisopropylamino, ethylcyclopropylamino,ethylbutylamino, ethylisobutylamino, ethyl-sec-butylamino,ethyl-tert-butylamino, ethylpentylamino, ethylhexylamino,propylisopropylamino, propylcyclopropylamino, propylbutylamino,propylisobutylamino, propyl-sec-butylamino, propyl-tert-butylamino,propylpentylamino, propylhexylamino, isopropylcyclopropylamino,isopropylbutylamino, isopropylisobutylamino, isopropyl-sec-butylamino,isopropyl-tert-butylamino, isopropylpentylamino, isopropylhexylamino,cyclopropylbutylamino, cyclopropylisobutylamino,cyclopropyl-sec-butylamino, cyclopropyl-tert-butylamino,cyclopropylpentylamino, cyclopropylhexylamino, butylisobutylamino,butyl-sec-butylamino, butyl-tert-butylamino, butylpentylamino,butylhexylamino, isobutyl-sec-butylamino, isobutylpentylamino,isobutylhexylamino, sec-butylpentylamino, sec-butylhexylamino,tert-butylpentylamino, and tert-butylhexylamino. A “mono- or di-loweralkylaminoalkyl group” refers to a lower alkyl group substituted by one“mono- or di-lower alkylamino group” described above.

A “hydroxyaminocarbonyl group” refers to an aminocarbonyl groupsubstituted by a hydroxyl group.

A “carboxyalkylsulfinyl group” refers to a sulfinyl group to which a“carboxyalkyl group” is bonded. A “lower alkoxycarbonylalkylsulfinylgroup” refers to a group in which —OH of the carboxyl group of a“carboxyalkylsulfiny group” is substituted by a lower alkoxy group asdescribed above.

As used herein, “alkylene” refers to a C1-C8 straight or branchedalkylene group, and examples thereof include methylene, ethylene,propylene, methylmethylene, butylene, dimethylmethylene, andpentamethylene.

An “aromatic hydrocarbon” refers to a C6-C14 aromatic hydrocarbon, andexamples thereof include benzene and naphthalene. An “aromaticheterocyclic ring” refers to a 5- to 14-membered monocyclic or condensedring having one to three nitrogen atoms, oxygen atoms, or sulfur atomsas hetero atoms, and examples thereof include pyridine, furan, andthiophene.

Preferably, R₁ in formula (I) is a hydrogen atom, a C1-C8 straight orbranched alkyl group, a C1-C8 straight or branched alkoxyl group, or ahalogen atom. More preferably, R₁ is a hydrogen atom, a C1-C5 straightor branched alkyl group, a C1-C5 straight or branched alkoxyl group, ora halogen atom. Most preferably, R₁ is a hydrogen atom, a methyl group,a methoxyl group, or a halogen atom.

Preferably, n is 0 or 1, and more preferably, n is 1.

Preferably, R₂ is a group represented by —CO—R₈ (R₈ is the same asdescribed above). Preferably, R₈ is C1-C8 straight, branched, or cyclicalkyl which may be substituted by a halogen atom, C2-C8 alkenyl, C1-C8alkoxyl, mono- or di-(C1-C8)alkoxy-(C1-C8)alkyl, adamantyl,bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl,6,6-dimethyl-bicyclo[3.1.1]heptan-2-yl,6,6-dimethyl-bicyclo[3.1.1]hepta-2-en-2-yl, benzyloxyl, phenyl, pyridyl,piperazinyl, pyrrolydinyl, furyl, thienyl (wherein any one ofphenylpyridyl, piperidinyl, pyrrolydinyl, furyl, and thienyl groups maybe substituted by one or two substituents selected from the groupconsisting of a C1-C8 alkyl group, a C1-C8 alkoxyl group, a halogenatom, an amino group, and a nitro group), or —N(R₉ )R₁₀ (wherein each ofR₉ and R₁₀ represents a hydrogen atom, C1-C8 alkyl, hydroxy-C1-C8 alkyl,mono- or di-(C1-C8)alkylamino-(C1-C8)alkyl, phenyl, pyridyl,piperidinyl, pyrrolydinyl, furyl, or thienyl). More preferably, R, isC1-C8 alkyl which may be substituted by a halogen atom, C1-C8 alkoxyl,C2-C3 alkenyl, phenyl, pyridyl, furyl, thienyl (wherein the phenyl,pyridyl, furyl, or thienyl may each be substituted by a C1-C8 alkylgroup, a C1-C8 alkoxyl group, or a halogen atom).

Preferably, R₃ is a hydrogen atom; C2-C8 alkenyl; straight, branched, orcyclic C1-C8 alkyl which may be substituted by a halogen atom; C1-C8alkylsulfonyl; mono- or di-(C1-C8)alkoxy-(C1-C8)alkyl; phenyl which mayhave a substituent; —CH(R₆)R₇; or —COR₈ (R₆, R₇, and R₈ are the same asdescribed above). More preferably, R₃ is C2-C8 alkenyl, straight,branched, or cyclic C1-C8 alkyl which may be substituted by a halogenatom, phenyl (which may be substituted by C1-C8 alkyl, C1-C8 alkoxyl, ahalogen atom, an amino group, or a nitro group), or a —COR₈ (R₈ is thesame as described above).

Preferably, Ar is a benzene ring.

Preferably, at least one of R₄ and R₅ is a group represented by—Y—COOR₁₁ (Y and R₁₁ are the same as described above).

More preferably, R₄ is a hydrogen atom, C1-C8 alkyl, halogen, C1-C8alkoxyl, and R⁵ is preferably —Y—COOR₁₁.

Examples of the group represented by —Y—COOR₁₁ include carboxyl,alkoxycarbonyl, benzyloxycarbonyl, carboxylalkyl, alkoxycarbonylalkyl,benzyloxycarbonylalkyl, carboxyalkyloxyl, alkoxycarbonylalkyloxyl,benzyloxycarbonylalkyloxyl, carboxyalkylthio, alkoxycarbonylalkylthio,benzyloxycarbonylalkylthio, carboxyalkylsulphinyl,alkoxycarbonylalkylsulphinyl, benzyloxycarbonylalkylsulphinyl,hydroxyaminocarbonyl, alkoxyaminocarbonyl, benzyloxyaminocarbonyl,carboxyalkylcarbamoyl, alkoxycarbonylalkylcarbamoyl, andbenzyloxycarbonylalkylcarbamoyl. Among these groups, “alkyl” and“alkoxyl” are preferably those of C1-C8 straight or branched, morepreferably C1-C6 straight or branched.

Examples of an alkoxycarbonyl group include a carbonyl group having a“lower alkoxyl group” as described above.

Examples of a “carboxyalkyl group” include carboxymethyl,1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2-carboxypropyl,3-carboxypropyl, 1-carboxy-1-methylethyl, 2-carboxy-1-methylethyl,1-carboxycyclopropyl, 2-carboxycyclopropyl, 1-carboxybutyl,2-carboxybutyl, 3-carboxybutyl, 4-carboxybutyl,1-carboxy-2-methylpropyl, 2-carboxy-2-methylpropyl,3-carboxy-2-methylpropyl, 1-carboxy-1-methylpropyl,2-carboxy-1-methylpropyl, 3-carboxy-1-methylpropyl,2-carboxy-1,1-dimethylethyl, 1-carboxycyclobutyl, 2-carboxycyclobutyl,1-carboxy-1-cyclopropylmethyl, (1-carboxycyclopropyl)methyl,(2-carboxycyclopropyl)methyl, 1-carboxymethylcyclopropyl,1-methyl-2-carboxycyclopropyl, 2-carboxymethylcyclopropyl,2-carboxy-2-methylcyclopropyl, 2-carboxy-3-methylcyclopropyl,1-carboxypentyl, 2-carboxypentyl, 3-carboxypentyl, 4-carboxypentyl,5-carboxypentyl, 1-carboxymethylbutyl, 1-carboxy-1-methylbutyl,2-carboxy-1-methylbutyl, 3-carboxy-1-methylbutyl,4-carboxy-1-methylbutyl, 2-carboxymethylbutyl, 1-carboxy-2-methylbutyl,2-carboxy-2-methylbutyl, 3-carboxy-2-methylbutyl,4-carboxy-2-methylbutyl, 3-carboxy-3-methylbutyl,2-carboxy-3-methylbutyl, 3-carboxy-3-methylbutyl,4-carboxy-3-methylbutyl, 1-carboxyhexyl, 2-carboxyhexyl, 3-carboxyhexyl,4-carboxyhexyl, 5-carboxyhexyl, 6-carboxyhexyl, 1-carboxycyclohexyl,2-carboxycyclohexyl, 3-carboxycyclohexyl, and 4-carboxycyclohexyl.Examples of a “carboxyalkylthio” include a sulfur atom having a“carboxyalkyl group” described above bonded thereto.

Examples of an “alkoxycarbonylalkyl group” include a lower alkyl groupsubstituted by one “lower alkoxycarbonyl” as described above. Examplesof a “benzyloxycarbonylalkyl group” include a lower alkyl groupsubstituted by one benzyloxycarbonyl group. Therefore, an“alkoxycarbonylalkylthio group” refers to a group formed of a sulfur anda “lower alkoxycarbonylalkyl group” described above bonded thereto. A“benzyloxycarbonylalkylthio group” refers to a group formed of a sulfuratom and a “benzyloxycarbonylalkyl group” described above bondedthereto; an “alkoxycarbonylalkylcarbamoyl group” refers to a groupformed of a carbamoyl group and a “lower alkoxycarbonylalkyl group”described above bonded thereto; and a “carboxyalkylcarbamoyl group”refers to a group formed of a carbamoyl group and a “carboxyalkyl group”described above bonded thereto.

A “carboxyalkyloxyl group” refers to a group formed of an oxygen atomand a “carboxyalkyl group” described above bonded thereto; an“alkoxycarbonylalkoxyl group” refers to a group formed of a loweralkoxyl group and one “lower alkoxycarbonyl group” described abovebonded thereto; and a benzyloxycarbonylalkoxyl group refers to a groupformed of one of the above-described alkoxyl groups and abenzyloxycarbonyl group bonded thereto.

Among these groups represented by —Y—COOR₁₁, R₅ is preferably carboxyl,C1-C8 alkoxycarbonyl, benzyloxycarbonyl, carboxy-(C1-C8)alkyl,(C1-C8)alkoxycarbonyl-(C1-C8)alkyl, benzyloxycarbonyl-(C1-C8)alkyl,carboxy-(C1-C8)alkylthio, (C1-C8)alkoxycarbonyl-(C1-C8)alkylthio, orbenzyloxycarbonyl-(C1-C8)alkylthio, more preferably, carboxyl orcarboxymethylthio.

The compounds (I) of the present invention can be converted into saltsaccording to conventional methods. Examples of the salts include thoseformed by addition of inorganic acids, such as hydrochlorides, sulfates,nitrates, phosphates, hydrobromides, or hydroiodides; those formed byaddition of organic acids, such as acetates, oxalates, malonates,succinates, maleates, fumarates, hibenzates, lactates, malates,citrates, tartrates, methanesulfonate, and ethanesulfonates; inorganicsalts such as sodium salts, potassium salts, calcium salts, andmagnesium salts; and organic salts such as ammonium salts, pyridinesalts, triethylamine salts, ethanolamine salts, (R) or (S) isomericα-phenethylamine salts, benzylamine salts, and 4-methylbenzylaminesalts.

The present invention encompasses not only the compounds (I) of thepresent invention and salts thereof, but also a variety of solvates suchas hydrates, and compounds having a variety of crystal structures.Further, the present invention encompasses racemates, diastereomers,mixtures of diastereomers, and optical isomers of compounds (I).

The compounds (I) of the present invention can be produced through avariety of synthetic methods in consideration of characteristics of thefundamental structure and radicals thereof. Typical production methodswill be described below.

Process A

(wherein A represents a tert-butoxycarbonyl group or a benzyloxycarbonylgroup; B represents a halogen atom; E represents a halogen atom; Grepresents an amino group, an isocyanato group, or a carboxyl group; andR₁, R₂, R₃, R₄, R₅, Ar, and n represent the same as defined above).

Step A1

Compound (III) is reacted with 1,5-benzodiazepine compound (II), tothereby obtain 5-substituted compound (IV). The reaction may beperformed in the presence or in the absence of a base. Examples of thebase include organic bases such as pyridine and triethylamine, and ifnecessary inorganic bases such as potassium carbonate, potassiumbicarbonate, sodium carbonate, and sodium bicarbonate may optionally beused. No particular limitation is imposed on the solvents which are usedfor the reaction so long as they do not affect the reaction, andhalogenated solvents such as 1,2-dichloroethane and methylene chlorideare used. When R₃ is a lower alkyl group, a lower alkenyl group, or agroup represented by —CHR₆R₇, alcoholic solvents such as methanol andethanol and polar solvents such as N,N-dimethylformamide anddimethylsulfoxide may also be used. The reaction may be performed withinthe temperature range of 0° C. to reflux temperature. In this step, anisocyanato compound (R₃-NCO) may be used as compound (III). In thiscase, a compound having an amido bond at the 5-position of thebenzodiazepine ring is obtained.

Step A2

Compound (V) is reacted with 5-substituted compound (IV), to therebyobtain 1,5-substituted compound (VI). The reaction is typicallyperformed by successively adding to 5-substituted compound (IV) a basesuch as sodium hydride, sodium hydroxide, or sodium carbonate; compound(V); and an optional phase-transfer catalyst such as tetrabutylammoniumbromide. No particular limitation is imposed on the solvents which areused for the reaction so long as they do not affect the reaction, andthere may typically be used etheric solvents such as tetrahydrofuran anddioxane; toluene; N,N-dimethylformamide; and dimethylsulfoxide. Thereaction may also be performed in a dual-phase system such as awater-toluene system by use of a phase-transfer catalyst such astetrabutylammonium. The reaction may be performed at 0-150° C.

This step is performed after Step A1, and may alternatively be performedafter completion of Steps A1, A3 and A4.

Step A3

When A of 1,5-substituted compound (VI) is a benzyloxycarbonyl group,compound (VI) is hydrocracked, to thereby obtain amine compound (VII).The reaction is typically performed by adding palladium carbon orpalladium hydroxide in a hydrogen atmosphere at ambient pressure and 0°C.-100° C. No particular limitation is imposed on the solvents which areused for the reaction so long as they do not affect the reaction, andalcoholic solvents such as methanol and ethanol and ethyl acetate may beused. Alternatively, adding to compound (VI) an acid such as ahydrobromic acid-acetic acid solution produces amine compound (VII). Thereaction is performed at 0° C.-100° C. When A of compound (VI) is atert-butoxycarbonyl group, addition of an acid such as hydrochloric acidor trifluoroacetic acid produces amine compound (VII). The reaction istypically performed at 0° C.-100° C. Alcoholic solvents such as methanoland ethanol; halogenated solvents such as chloroform; and ethericsolvents such as dioxane and diethyl ether are used as a solvent.

Step A4

Compound (VIII) is reacted with amine compound (VII), to thereby derivethe compound of the present invention (I). When G of compound (VIII) isan isocyanato group, no particular limitation is imposed on the solventswhich are used for the reaction so long as they do not affect thereaction, and there may typically be used etheric solvents such astetrahydrofuran; hydrocarbon solvents such as toluene and benzene;halogenated solvents such as methylene chloride, 1,2-dichloroethane, andchloroform; and polar solvents such as N,N-dimethylformamide andacetonitrile. The reaction is performed within the temperature range of0° C. to reflux temperature. When G of compound (VIII) is an aminogroup, the reaction is performed by treating amine compound (VII) with1,1′-carbonyldiimidazole and, subsequently adding triethylamine andcompound (VIII). Alternatively, the reaction is performed by adding1,1′-carbonyldiimidazole and triethylamine to compound (VIII), andsubsequently adding compound (VII). Alternatively, the reaction isperformed by converting compound (VIII) to an isocyanato derivative inthe presence of triphosgene and an organic base such as triethylamine,and subsequently adding amine compound (VII). When G of compound (VIII)is a carboxyl group, the reaction is performed by addingdiphenylphosphoryl azide and an organic base such as triethylamine toinduce Curtius rearrangement reaction to thereby derive to an isocyanatoderivative, and subsequently adding compound (VII). No particularlimitation is imposed on the solvents which are used for the reaction solong as they do not affect the reaction, and there may typically be usedetheric solvents such as tetrahydrofuran and dioxane; halogenatedsolvents such as methylene chloride; and hydrocarbon solvents such astoluene and benzene. The reaction is performed within the temperaturerange of 0° C. to reflux temperature, while Curtius rearrangementreaction is preferably performed within the temperature range of 50° C.to reflux temperature so as to obtain a satisfactory result.

Process B

Among the compounds (I) of the present invention, compounds in which R₂is an optionally substituted phenyl group and n is 0 can be producedthrough the following process:

(wherein A, B, G, R₁, R₃, R₄, R₅, and Ar represent the same as definedabove).

Step B1

Iodobenzene is reacted with compound (II), to thereby obtain 1-phenylcompound (IX). The reaction is typically performed by adding a base suchas potassium carbonate in the presence of copper and copper iodidewithin the temperature range of 0° C. to reflux temperature. A solventsuch as N,N-dimethylformamide is used for the reaction.

Step B2

Compound (III) is reacted with 1-phenyl compound (IX), to thereby obtain1-phenyl-5-substituted compound (X). The reaction is performed in amanner similar to Step A1.

Step B3

When A of 1-phenyl-5-substituted compound (X) is a benzyloxycarbonylgroup, compound (X) is hydrogenated to thereby obtain 1-phenylaminecompound (XI). Alternatively, an acid such a hydrobromic acid-aceticacid solution is added to compound (X), to thereby obtain 1-phenylaminecompound (XI). Furthermore, when A of compound (X) is atert-butoxycarbonyl group, an acid such a hydrochloric acid-dioxanesolution is added, to thereby obtain 1-phenylamine compound (XI). Allthe reactions are performed similarly to Step A3.

Step B4

Compound (VIII) is reacted with 1-phenylamine compound (XI), to therebyderive compound (I) of the present invention. The reaction is performedsimilarly to Step A4.

Process C

Among the compounds (I) of the present invention, compounds in which R₃is an optionally substituted phenyl group can be produced by producingcompound (Iva) through the following process; performing Step A2 ofProcess A using compound (Iva) instead of compound (IV); andsubsequently performing Steps A3 and A4, or performing Step B1 ofProcess B using compound (IVa) instead of compound (II); andsubsequently performing Steps B3 and B4.

(wherein A, E, and R₁ represent the same as defined above and Jrepresents a phenyl group which may be substituted).

In Step C9; i.e., protection reaction of an amino group, when A is atert-butoxycarbonyl group, the protection reaction is performed byadding di-tert-butyl dicarbonate to thereby obtain compound (IVa),whereas when A is a benzyloxycarbonyl group, the protection reaction isperformed by adding benzyloxycarbonyl chloride to thereby obtaincompound (IVa).

Process D

(wherein B, E, G, R₁, R₂, R₃, R₄, R₅, and Ar represent the same asdefined above).

Step D1

Compound (IIa) is reacted with benzyloxycarbonyl chloride, to therebyobtain a 5-benzyloxycarbonyl compound (XII). The reaction is performedtypically in the presence or in the absence of a base. Examples of thebase include organic bases such as pyridine and triethylamine, andinorganic bases such as potassium carbonate, potassium bicarbonate,sodium carbonate, and sodium bicarbonate may optionally be used asdesired. No particular limitation is imposed on the solvents which maybe used for the reaction so long as they do not affect the reaction, andhalogenated solvents such as 1,2-dichloroethane and methylene chlorideare used. The reaction may be performed in the range of 0° C. to refluxtemperature.

Step D2

Compound (V) is reacted with 5-benzyloxycarbonyl compound (XII), tothereby obtain a 1,5-substituted compound (XIII). The reaction isperformed similarly to Step A2.

Step D3

Acid such as hydrochloric acid or trifluoroacetic acid is added to1,5-substituted compound (XIII), to thereby obtain amine compound (VIV).The reaction is typically performed in the range of 0° C. to 100° C.Examples of the solvent include alcohol such as methanol and ethanol,halogenated solvents such as chloroform, and etheric solvents such asdioxane and diethyl ether.

Step D4

Amine compound (XV) is reacted with compound (VIII), to thereby deriveto urea compound (XV). The reaction is performed similar to Step A4.

Step D5

Urea compound (XV) is hydrocracked, to thereby obtain a 5-amine compound(XVI). The reaction is typically performed by adding palladium carbon orpalladium hydroxide in a hydrogen atmosphere at ambient pressure and 0°C.-100° C. No particular limitation is imposed on the solvents which maybe used for the reaction so long as they do not affect the reaction, andalcoholic solvents such as methanol and ethanol and ethyl acetate may beused. Alternatively, addition of an acid such as a hydrobromicacid-acetic acid solution to (XV) produces 5-amine compound (XVI). Thereaction is typically performed at 0° C.-100° C.

Step D6

5-Amine compound (XVI) is reacted with compound (III), to thereby obtaincompound (I) of the present invention. The reaction is typicallyperformed similarly to Step A1.

Process E

Among the compounds (I) of the present invention, compounds in which R₃is a phenyl group, a cyclohexyl group, a cyclopentyl group, acycloheptyl group, or a cyclooctyl group can be produced through thefollowing process: compound (IIa) is converted to (IVb) or (IVc) by theprocess shown below; reaction is allowed to proceed by use of (IVb) or(IVc), instead of (IV) used in Step A2 of Process A; and a similarreaction is carried out as in Steps A3 and A4.

(wherein m represents a number of 1 to 4; and R₁ and E represent thesame as defined above).

One type of compound (I) of the present invention can be transformed toanother type of compound (I) of the present invention through additionalhydrolysis, solvolysis, hydrocracking, or hydrogenation. When R₄ or R₅is a group having a carboxyl group, a desired type of compound (I) ofthe present invention can be obtained through reaction with a condensingagent (such as 1-ethyl-3-(3-dimethylamino)carbodiimide,dicyclohexylcarbodiimide, or 2-chloro-1,3-dimethylimidazolium chloride)and a reagent (such as tetronic acid, thiotetronic acid, primary orsecondary amine, amino acid ester, or alcohol).

The thus-produced compound (I) of the present invention is isolated inits free form or as a salt, and then purified. Isolation andpurification are suitably performed by choosing from among routineprocedures such as extraction, condensation, evaporation,crystallization, filtration, recrystallization, pulverization, andchromatography. Also, compound (I) of the present invention or anoptically active intermediate can be produced by use of suitablestarting material compounds, or through generally-employed racemicresolution. Examples of racemic resolution include a method in which thecompound is transformed to a diastereomer salt through reaction with atypical optically active compound such as dibenzoyl tartarate,pyroglutamic acid, or α-phenethylamine, and subjected to opticalresolution; or a method in which the compound is transformed todiastereomer compound, followed by separation and performance of Edmandecomposition reaction.

The compound (I) of the present invention or salts thereof can beadministered orally or parenterally. For oral administration, thecompound of the present invention may be formed into solid preparationssuch as tablets, powder, and capsules, or into liquid preparations suchas solutions, suspensions, and emulsions by use of proper additivesincorporated thereto. Examples of the additives include excipients suchas lactose, mannitol, corn starch, and crystalline cellulose; binderssuch as cellulose derivatives, acacia, and gelatin; disintegrators suchas carboxymethylcellurose-Ca; lubricants such as talc, magnesiumstearate.

For parenteral administration, the compound of the present invention maybe formed into a liquid formulation for injection through incorporationof liquid such as water, ethanol, or glycerin.

The dose of the compound (I) of the present invention or salts thereofwhich is needed for the prevention or treatment of the aforementioneddiseases varies depending on the dosage form, manner of administration,age, and pathological conditions. In the case of oral administration,the dose is typically 1-1,000 mg, preferably 5-500 mg, per day for anadult, which dose is preferably divided 2-3 times a day.

As described hereinbelow, compounds (I) of the present invention orsalts thereof exhibit strong gastrin and/or CCK-B receptor antagonism aswell as strong action of suppressing secretion of gastric acid, andtherefore, they are useful for treatment, amelioration, and preventionof the diseases and disorders in which such actions are involved, whichinclude gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis,pancreatitis, Zollinger-Ellison syndrome, vacuolating G-cellhyperplasia, basal-mucous-membrane hyperplasia, inflammation of thegallbladder, attack of biliary colic, motor disorders of alimentarycanal, irritable bowel syndrome, certain types of tumors, eatingdisorders, anxiety, panic disorder, depression, schizophrenia,Parkinson's disease, tardive dyskinesia, Gilles de la Tourette syndrome,drug dependence, and drug-withdrawal symptoms; and induction of painrelief or facilitation of induction of pain relief by use of an opioiddrug.

EXAMPLES

The present invention will next be described in more detail by way ofexamples, which should not be construed as limiting the inventionthereto.

Examples of producing intermediates of compound (I) of the presentinvention are provided as Referential Examples.

Referential Example 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1

Preparation of2-tert-butoxycarbonylamino-3-benzyloxycarbonylaminopropionic acid

2-Amino-3-benzyloxycarbonylaminopropionic acid (4.6 g) preparedaccording to a known method (Chem. Pharm. Bull., Vol. 7, 616 (1959)) wasadded to an aqueous solution (100 ml) of sodium carbonate (2.05 g).Di-tert-butyldicarbonate (4.68 g) in tetrahydrofuran (100 ml) was addedthereto and the resultant mixture was stirred overnight at roomtemperature. The mixture was washed with ethyl acetate, and 1Nhydrochloric acid was added to the aqueous layer to adjust pH to 3. Theresultant mixture was extracted with methylene chloride. The organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure, to thereby obtain 6.51 g of the titlecompound.

¹H-NMR(CDCl₃) δ: 1.43(9H, S), 3.45˜3.70(2H, m), 4.20˜4.42(1H, m),5.08(2H, s), 5.50(1H, brs), 5.73(1H, brs), 7.32(5H, s), 8.27(1H, brs)

Step 2

Preparation of2-tert-butoxycarbonylamino-3-(2-nitrophenyl)aminopropionic acid

2-tert-Butoxycarbonylamino-3-benzyloxycarbonylaminopropionic acid (1.06g) was dissolved in methanol (50 ml). 10% Palladium carbon (100 mg) wasadded thereto, and the mixture was stirred at room temperature for twohours under hydrogen atmosphere. The resultant mixture was filtered, andthe filtrate was concentrated under reduced pressure to thereby obtain540 mg of 3-amino-2-tert-butoxycarbonylaminopropionic acid, which wasdissolved in ethanol (50 ml). Potassium carbonate (365 mg) and2-fluoronitrobenzene (377 mg) were added thereto, and the mixture wasrefluxed with heat for 3 hours. The resultant mixture was concentratedunder reduced pressure. Water was added to the residue, and the residuewas washed with diethyl ether. 1N Hydrochloric acid was added to theaqueous layer to adjust pH to 3. The resultant mixture was extractedwith methylene chloride. The organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure, tothereby obtain 530 mg of the title compound.

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 3.60˜3.95(2H, m), 4.50˜4.70(1H, m),5.37(1H, brs), 6.67˜6.73(1H, m), 6.96˜7.03(1H, m), 7.43˜7.49(1H, m),8.13˜8.19(1H, m), 8.26(1H, brs), 11.50(1H, brs)

Step 3

Preparation of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-tert-Butoxycarbonylamino-3-(2-nitrophenyl)aminopropionic acid (325 mg)was dissolved in methanol (50 ml). 10% Palladium carbon (50 mg) wasadded thereto, and the mixture was stirred at room temperature for onehour under hydrogen atmosphere. The resultant mixture was filtrated, andthe filtrate was concentrated under reduced pressure to thereby obtain2-tert-butoxycarbonylamino-3-(2-aminophenyl)aminopropionic acid, whichwas suspended in toluene (30 ml), and the mixture was refluxed with heatby use of a Dean-Stark so as to remove water for 3 hours. The resultantmixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (chloroform:methanol=20:1).Diisopropyl ether was added thereto for crystallization, and the mixturewas filtrated to thereby obtain 210 mg of the title compound (yield:76%).

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 3.39˜3.47(1H, m), 3.80˜3.98(2H, m),4.44˜4.55(1H, m), 5.73(1H, brs), 6.71˜6.88(3H, m), 6.97˜7.03(1H, m),7.82(1H, brs)

Referential Example 2

Preparation of2-oxo-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2 g) obtained from Referential Example 1 was dissolved in chloroform(50 ml). 4N HCl-dioxane solution (20 ml) was added thereto, and themixture was stirred at 50° C. for one hour. After the reaction mixturewas allowed to cool, crystals so precipitated were collected byfiltration. The crystals were dissolved in water (50 ml), andbenzyloxycarbonylchloride (1.29 g) in tetrahydrofuran (30 ml) was addedthereto. The mixture was cooled on ice, and 1N aqueous sodium hydroxide(22 ml) was added dropwise. The mixture was stirred for one hour. Aftercompletion of reaction, ethyl acetate was added thereto, and theresultant mixture was extracted, washed with saturated brine, and driedover anhydrous sodium sulfate. Ethanol was added for crystallization, tothereby obtain 1.49 g of the title compound.

¹H-NMR(CDCl₃) δ: 3.44(1H, t), 3.81˜4.02(2H, m), 4.55˜4.62(1H, m),5.10(2H, s), 6.00(1H, d), 6.72˜6.89(3H, m), 6.97˜7.05(1H, m),7.26˜7.39(5H, m), 7.74(1H, s)

Referential Example 3

Preparation of2-oxo-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1

Preparation of N-(2-nitrophenyl)-N-(2-cyanoethyl)aniline

Acrylonitrile (210 ml) and 40% benzyltrimethylammoniumhydroxide inmethanol (1.5 ml) were added to 2-nitrodiphenylamine (100 g), and themixture was refluxed with heat for one hour. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=2:1) to therebyobtain 47.7 g of the titled compound as a red solid.

¹H-NMR(CDCl₃) δ: 2.80(2H, t), 4.08(2H, t), 6.63(2H, dq), 6.89(1H, tt),7.16˜7.28(2H, m), 7.40(1H, dt), 7.53(1H, dd), 7.68(1H, dt), 7.87(1H, dd)

Step 2

Preparation of 3-[N-(2-aminophenyl)-N-phenyl]aminopropionic acid

10% palladium carbon (4.7 g) was added toN-(2-nitrophenyl)-N-(2-cyanoethyl)aniline (47.1 g) suspended in ethanol(500 ml), and the resultant mixture was stirred for one hour and 30minutes under hydrogen atmosphere, under ambient pressure, at roomtemperature. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inethanol (400 ml). An aqueous solution (700 ml) of potassium hydroxide(79.1 g) was added thereto, and the resultant mixture was refluxed forfour hours with heat. After completion of reaction, the reaction mixturewas allowed to cool. Concentrated hydrochloric acid and 1N hydrochloricacid were added thereto so as to adjust pH to 4. Crystals soprecipitated were collected by filtration, to thereby obtain 39.9 g ofthe title compound as a gray solid (yield: 88.5%).

¹H-NMR(DMSO-d₆) δ: 2.40˜2.56(2H, m), 3.67˜3.80(2H, m), 4.69˜5.02(2H,br), 6.48˜6.66(4H, m), 6.79(1H, dd), 6.90(1H, dd), 6.98˜7.15(3H, m)

Step 3

Preparation of 2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

o-Xylene (1 litter) was added to3-[N-(2-aminophenyl)-N-phenyl]aminopropionic acid (108.6 g), and theresultant mixture was refluxed with heat by use of a reflux condenserequipped with a Dean-Stark water separator. The reaction mixture wasallowed to cool, and crystals so precipitated were collected byfiltration, to thereby obtain 93.0 g of the title compound as a graysolid (yield: 92.1%).

¹H-NMR(CDCl₃) δ: 2.67(2H, t), 4.04(2H, t), 6.76(2H, d), 7.07(1H, t),7.15˜7.28(6H, m), 7.67(1H, brs)

Step 4

Preparation of1-methoxymethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

In an argon stream,2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (40.4 g) wasadded to 60% sodium hydride (8.84 g) suspended in absolutetetrahydrofuran (500 ml) at 0° C. The mixture was stirred for one hourat 0° C., and chloromethyl methyl ether (20.5 g) was added thereto,followed by stirring for two hours and 30 minutes at room temperature.The reaction mixture was concentrated under reduced pressure, andice-water was added thereto, followed by extraction with chloroform. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, tothereby obtain 47.4 g of the title compound as a yellow oil (yield:98.8%).

¹H-NMR(CDCl₃) δ: 2.64(2H, t), 3.34(3H, s), 3.96(2H, t), 5.21(2H, s),6.79(2H, d), 6.86(1H, t), 7.15˜7.28(5H, m), 7.44˜7.50(1H, m)

Step 5

Preparation of1-methoxymethyl-2-oxo-3-hydroxyamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Potassium tert-butoxide (57.8 g) was added to1-methoxymethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(29.1 g) in absolute toluene (1 litter) at 0° C. The resultant mixturewas stirred for 30 minutes at 0° C., and tert-butyl nitrite (31.9 g) wasadded thereto, followed by stirring for 18 hours at room temperature.Ice-water was added to the reaction mixture for separation of layers,and the aqueous layer was extracted with ethyl acetate. The organiclayers were combined, washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (chloroform:methanol=25:1), to thereby obtain 22.8 g ofthe title compound as a light brown oily substance (yield: 71.1%).

¹H-NMR(CDCl₃) δ: 3.42 and 3.44(3H, each s), 4.58 and 4.78(1H, each br,brs), 5.25 and 5.28(2H, each s), 6.78˜7.00(3H, m), 7.10˜7.65(6H, m),7.91(1H, brs)

Step 6

Preparation of1-methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

To1-methoxymethyl-2-oxo-3-hydroxyamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(41.4 g) in absolute tetrahydrofuran (500 ml) were added n-propylisocyanate (28.3 g) and triethylamine (33.7 g). The resultant mixturewas refluxed for three hours with heat. The reaction mixture wasconcentrated under reduced pressure, and the residue was crushed inisopropyl ether and collected by filtration, to thereby obtain 33.4 g ofthe title compound (yield: 63.3%).

¹H-NMR(CDCl₃) δ: 0.90(3H, t), 1.45˜1.60(2H, m), 3.10˜3.23(2H, m),3.43(3H, s), 4.20˜5.10(2H, m), 5.28(2H, brs), 5.53˜5.64(1H, m), 6.80(2H,d), 6.95(1H, t), 7.12˜7.33(5H, m), 7.52(1H, dd)

Step 7

Preparation of1-methoxymethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinehydrochloride

10% Palladium carbon (2.0 g) was added to1-methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(14.2 g) suspended in methanol (200 ml), and the resultant mixture wasstirred for two hours under hydrogen atmosphere (3 kg/cm²) at roomtemperature. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform:methanol=20:1), to thereby obtaina yellow oily substance. The substance was dissolved in ether, and 4Nhydrochloric acid-dioxane (10 ml) was added thereto. Crystals soprecipitated were collected by filtration, to thereby obtain 8.28 g ofthe title compound as a white solid (yield: 69.3%).

¹H-NMR(CDCl₃) δ: 3.16(3H, s), 4.21˜4.49(3H, m), 5.10(2H, s); 6.80(2H,d), 6.87(1H, t), 7.15˜7.27(5H, m), 7.40˜7.47(1H, m), 8.99(2H, br)

Step 8

Preparation of2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

25% Hydrobromic acid-acetic acid (150 ml) was added to1-methoxymethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinehydrochloride (12.2 g). The resultant mixture was stirred for 30 minutesat room temperature. Ether was added thereto, and solid matter soprecipitated was collected by filtration, to thereby obtain2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinehydrobromide. Water (100 ml) was added thereto so as to obtain asuspension. Benzyl chloroformate (6.23 g) in tetrahydrofuran (100 ml)and 1N aqueous sodium hydroxide (75 ml) were added to the suspensionunder cooling on ice, followed by stirring for one hour at roomtemperature. The reaction mixture was concentrated under reducedpressure, and water was added thereto, followed by extraction withmethylene chloride. The organic layer was washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 9.6 g ofthe title compound (yield: 67.9 %).

¹H-NMR(CDCl₃) δ: 3.69(1H, dd), 4.32(1H, dd), 4.65(1H, dt), 5.09(2H, s),5.87(1H, d), 6.72(2H, d), 6.86(1H, t), 7.08˜7.40(11H, m), 7.75(1H, brs)

Referential Example 4

Preparation of2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Potassium carbonate (6.91 g) was added to a solution prepared bydissolving 3-amino-2-(tert-butoxycarbonyl)aminopropionic acid (5.11 g)and 4-fluoro-3-nitrotoluene (3.88 g) in ethanol (100 ml), and theresultant mixture was refluxed overnight. The reaction mixture wasallowed to cool, and filtrated. The filtrated mixture was concentratedunder reduced pressure. The residue was dissolved in water (200 ml), andwashed with ether. 1N Hydrochloric acid was added thereto so as toadjust pH to 3, followed by extraction with methylene chloride. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate so as to evaporate the solvent, to thereby obtain3-(2-nitro-4-methyl)anilino-2-tert-butoxycabonylaminopropionic acid.

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.26(3H, s), 3.55˜3.89(2H, m),4.45˜4.63(1H, m), 5.44(1H, d), 6.91(1H, d), 7.27(1H, d), 7.94(1H, s),8.14(1H, brs), 1.50(1H, brs)

The thus-obtained compound was dissolved in ethanol (200 ml), and 10%palladium carbon (1 g) was added thereto. The resultant mixture wasstirred for five hours under hydrogen atmosphere, under ambientpressure. The mixture was filtrated, and the filtrate was concentratedunder reduced pressure. Toluene was added thereto, and crystals soprecipitated were collected by filtration, to thereby obtain3-(2-amino-4-methyl)anilino-2-tert-butoxycabonylaminopropionic acid. Theacid was suspended in toluene (100 ml), and the suspension was refluxedovernight while water was removed by use of a Dean-Stark condenser.After reaction, the system was allowed to cool, and crystals soprecipitated were collected by filtration. The precipitated crystalswere washed with isopropyl ether, and dried in air, to thereby obtain1.66 g of the title compound (yield: 40%).

¹H-NMR(DMSO-d₆) δ: 1.36(9H, s), 2.17(3H, s), 3.25˜3.32(1H, m),3.43˜3.49(1H, m), 4.07˜4.18(1H, m) 5.30(1H d), 6.70˜6.76(3H, m),6.83(1H, d), 9.61(1H s)

Referential Example 5

Preparation of2-oxo-3-tert-butoxycarbonylamino-⁸-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

The procedure of Referential Example 4 was repeated except that1,4-difluoro-2-nitrobenzene was used instead of 4-fluoro-3-nitrotoluene,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 3.40(1H, t), 3.70(1H, brs), 3.90(1H, dd),4.46˜4.58(1H, m), 5.64(1H, brd), 6.66˜6.77(3H, m), 7.99(1H, s)

Referential Example 6

Preparation of(+)-2-oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

The procedure of Steps 1 to 3 of Referential Example 1 was repeated byuse of (R)-3-amino-2-benzyloxycarbonylaminopropionic acid [α]D (C=1.20,MeOH): +28.7°) produced according to a known method (Synthesis, 542(1989) and Chem. Pharm. Bull. vol. 7, 616 (1959)), to thereby obtain thetitle compound (optical purity: 96%ee, [α]D (C=1.0, CHCl₃): +5.9°)

Production examples of the compound (I) of the present invention willnext be described as Examples 1 to 176.

Example 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(700 mg) obtained from Reference Example 1 was suspended in1,2-dichloroethane (20 ml). Pyridine (237 mg) and pivaloyl chloride (362mg) were added thereto, and the mixture was refluxed for two hours.After the reaction mixture was allowed to cool, crystals thatprecipitated were collected by filtration, to thereby obtain 650 mg ofthe title compound (yield: 71%).

¹H-NMR(DMSO-d₆) δ: 0.88(9H, s), 1.34(9H, s), 3.39˜3.59(1H, m),3.98˜4.17(1H, m), 4.30˜4.58(1H, m), 7.10˜7.51(5H, m), 10.02(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

60% Sodium hydride (1.6 g) was suspended in tetrahydrofuran (100 ml),2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(7.23 g) was added thereto under ice-cooling, and the resultant mixturewas stirred for one hour. Subsequently, 2-bromo-2′-methylacetophenone(4.88 g) was added thereto, and the mixture was stirred at roomtemperature for one hour. The reaction mixture was concentrated underreduced pressure. Ice-water was added to the residue. The resultantmixture was extracted with methylene chloride. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andpurified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 7.8 g of the title compound (yield: 79%)

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.40(9H, s), 2.57(3H, s), 4.05(1H, dd),4.27(1H, t), 4.46(1H, d), 4.48˜4.63(1H, m), 5.51(1H, brs), 5.55(1H, d),7.24˜7.77(8H, m)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

4N HCl-dioxane solution (5 ml) was added to1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(540 mg) in ethanol (5 ml), and the mixture was stirred at 50° C. for 30minutes. The reaction mixture was concentrated under reduced pressure,and saturated aqueous sodium bicarbonate solution was added to theresidue, followed by extraction with methylene chloride. The extract wasdried over anhydrous sodium sulfate, to thereby obtain 411 mg of thetitled compound.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.64(2H, brs), 2.58(3H, s), 3.66˜3.83(2H,m), 4.26(1H, t), 4.37(1H, d), 5.68(1H, d), 7.20˜7.49(7H, m),7.76˜7.82(1H, m)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

1-(2-Toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(411 mg) was dissolved in tetrahydrofuran. m-Tolyl isocyanate (146 mg)was added thereto, and the resultant mixture was stirred at roomtemperature for 30 minutes. The solution was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 300 mg ofthe title compound.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 2.25(3H, s), 2.50(3H, s), 4.02(1H, dd),4.35(1H, d), 4.43(1H, d) 4.75˜4.95(1H, m), 5.49(1H, d), 6.13(1H, d),6.80(1H, d), 7.00˜7.50(11H, m), 7.66(1H, d)

MS(FAB)m/z: 527(MH⁺)

Example 2

Preparation of1-[1-[1-(2-toluoyl)ethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 2 of Example 1 was repeated except that2-bromo-2′-methylpropiophenone was used instead of2-bromo-2′-methylacetophenone. Subsequently, procedures of Step 3 and 4of Example 1 were performed, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.15(9H, s), 1.31(3H, d), 2.23(3H, s), 2.47(3H, s),4.01˜4.22(2H, m), 4.62˜4.71(1H, m), 5.71(1H, q), 6.15(1H, d),6.77˜7.83(13H, m)

MS(FAB)m/z: 541(MH⁺)

Example 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-Adamantylcarbonyl chloride (795 mg) and pyridine (0.33 ml) were addedto2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1 g) in anhydrous 1,2-dichloroethane (20 ml). The mixture was refluxedwith heat for one hour. After the reaction mixture was allowed to cool,crystals so precipitated were collected by filtration, to thereby obtain1.58 g of the titled compound as a white solid (yield: 99.8%).

¹H-NMR(DMSO-d₆) δ: 1.20˜1.84(24H, m), 3.25˜3.60(1H, m), 4.02˜4.17(1H,m), 4.30˜4.46(1H, m), 7.10˜7.35(4H, m), 7.40˜7.50(1H, m), 9.98(1H brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

To 60% sodium hydride (128 mg) suspended in anhydrous tetrahydrofuran(30 ml),2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas added at room temperature under argon atmosphere. The mixture wasstirred at room temperature for 30 minutes. Subsequently,2-bromo-2′-methylacetophenone (375 mg) in anhydrous tetrahydrofuran (10ml) was added thereto, and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated under reducedpressure. Ice-water (50 ml) was added to the residue, followed byextraction with chloroform. The organic layer was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. Ethanol was added to the residue forsolidification and collection by filtration, to thereby obtain 426 mg ofthe title compound as a white solid (yield: 46.6%).

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.44˜1.91(15H, m), 2.57(3H, s), 3.97(1H,dd), 4.21(1H, t), 4.41(1H, d), 4.48˜4.62(1H, m), 5.49(1H, d), 5.56(1H,d), 7.21˜7.51(8H, m), 7.75˜7.81(1H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

4N HCl-dioxane (5.0 ml) was added to1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(400 mg) in anhydrous ethanol (15 ml), and the mixture was stirred at50° C. for 15 minutes. The reaction mixture was concentrated underreduced pressure, and saturated aqueous sodium bicarbonate was added tothe residue, followed by extraction with methylene chloride. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure, to thereby obtain1-(2-toluoylmethyl)-2-oxo-3-amino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, this compound was dissolved in anhydrous tetrahydrofuran(10 ml), and m-tolyl isocyanate (0.10 ml) was added to thereto. Themixture was stirred at room temperature for 15 minutes. The solvent wasevaporated under reduced pressure. A solvent mixture of isopropyl etherand ethanol was added thereto for solidification and collection byfiltration, to thereby obtain 394 mg of the title compound (yield:93.1%).

Melting point: 263-265° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.40˜1.70(9H, m), 1.80˜1.93(6H, m), 2.25(3H, s),2.53(3H, s), 4.01(1H, dd), 4.30(1H, t), 4.43(1H, d), 4.76˜4.90(1H m),5.57(1H, d), 6.06(1H, d), 6.78˜7.50(12H, m), 7.68˜7.80(1H, d)

MS(FAB)m/z: 605(MH)⁺

Example 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinethat obtained from Referential Example 4 was used instead of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.97(9H, s), 1.40(9H, s), 2.39(3H, s), 3.87(1H, dd),4.35(1H, t), 4.43-4.50(1H, m), 5.40(1H, d), 6.95(1H, s), 7.06(1H, d),7.14(1H, d), 7.93(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.40(9H, s), 2.37(3H, s), 2.57(3H, s),3.93(1H, dd), 4.26(1H, t), 4.45(1H, d), 4.53-4.59(1H, m), 5.49(1H, d),5.51(1H, d), 7.04-7.15(3H, m), 7.28-7.34(2H, m), 7.42-7.48(1H, m),7.75-7.78(1H, m)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.02(9H, s), 1.66(2H, br), 2.38(3H, s), 2.59(3H, s),3.66-3.78(2H, m), 4.19-4.28(1H, m), 4.36(1H, d), 5.65(1H, d), 7.01(1H,s), 7.07-7.12(2H, m), 7.29-7.49(3H, m), 7.81(1H, m)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 4 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 217.5-219.5° C.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 2.25(3H, s), 2.38(3H, s), 2.51(3H, s),3.82(1H, dd), 4.33(1H, t), 4.41(1H, d), 4.77-4.88(1H, m), 5.47(1H, d),6.11(1H, d), 6.80(1H, d), 6.98-7.67(11H, m)

MS(FAB)m/z: 541(MH⁺)

Example 5

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-8-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.00(9H, s), 1.41(9H, s), 3.89(1H, dd), 4.37(1H, t),4.45-4.52(1H, m), 5.40(1H, d), 6.68-6.92(1H, m), 6.96-7.03(1H, m),7.22-7.27(1H, m), 8.08(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 1.41(9H, s), 2.57(3H, s), 3.97(1H, dd),4.28(1H, t), 4.42(1H, d), 4.54-4.60(1H, m), 5.50(1H, d), 5.55(1H, d),6.99-7.07(2H, m), 7.21-7.34(3H, m), 7.42-7.49(1H, m), 7.75-7.79(1H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-fluoro-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 2.28(3H, s), 2.52(3H, s), 4.01(1H, dd),4.35(1H, t), 4.40(1H, d), 4.77-4.89(1H, m), 5.51(1H, d), 5.96(1H, d),6.80-7.71(12H, m)

MS(FAB)m/z: 545(MH⁺)

Example 6

Preparation of1-(1-isobutyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 1

Preparation of1-isobutyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that 1-bromo-2-methylpropane wasused instead of 2-bromo-2′-methylacetophenone, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 0.94(3H, d), 0.97(3H, d), 1.07(9H, s), 1.40(9H, s),1.97-2.12(1H, m), 3.59-3.77(2H, m), 3.87-3.96(1H, m), 4.07-4.17(1H, m),4.33-4.45(1H, m), 5.50(1H, d), 7.15-7.44(4H, m)

Step 2

Preparation of1-(1-isobutyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-isobutyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 151.5-152.5° C.

¹H-NMR(CDCl₃) δ: 0.93(3H, d), 0.98(3H, d), 1.08(9H, s), 1.99-2.16(1H,m), 2.29(3H, s), 3.58(1H, dd), 3.79(1H, dd), 3.98(1H, dd), 4.20(1H, t),4.62-4.75(1H, m), 6.19(1H, d), 6.85(1H, d), 6.98-7.47(8H, m)

MS(FAB)m/z: 451(MH⁺)

Example 7

Preparation of1-(1-cyclopropylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 1

Preparation of1-cyclopropylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that bromomethylcyclopropylketone was used instead of 2-bromo-2′-methylacetophenone, tothereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.96-1.07(11H, m), 1.17-1.24(2H, m), 1.39(9H, s),1.98-2.06(1H, m), 3.92(1H, dd), 4.11(1H, d), 4.24(1H, t), 4.44-4.52(1H,m), 5.20(1H, d), 5.47(1H, d), 7.14-7.44(4H, m)

Step 2

Preparation of1-(1-cyclopropylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-cyclopropylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1 were performed,to thereby obtain the title compound.

Melting point: 184-186° C.

¹H-NMR(CDCl₃) δ: 0.91-1.20(13H, m), 2.07-2.17(1H, m), 2.27(3H, s),3.96(1H, dd), 4.06(1H, d), 4.36(1H, t), 4.70-4.81(1H, m), 5.27(1H, d),6.23(1H, d), 6.78(1H, d), 7.03-7.50(7H, m), 7.53(1H, s)

MS(FAB)m/z: 477(MH⁺)

Example 8

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-methoxymethylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of²-oxo-3-tert-butoxycarbonylamino-5-methoxymethylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that methoxyacetyl chloride wasused instead of pivaloyl chloride, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 3.29(3H, s), 3.52(1H, d), 3.85(1H, d),3.86-3.93(1H, m), 4.45-4.71(2H, m), 5.55(1H, brd), 7.17-7.44(4H, m),8.34(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methoxymethylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-methoxymethylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 2.46(3H, s), 3.36(3H, s), 3.80(1H, d),3.89(1H, d), 4.00(1H, d), 4.57-4.64(2H, m), 5.13(2H, ABq), 5.49(1H, d),7.25-7.36(5H, m), 7.39-7.48(2H, m), 7.71-7.76(1H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-methoxymethylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methoxymethylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 250-252° C. (decomposition)

¹H-NMR(CDCl₃) δ: 2.27(3H, s), 2.43(3H, s), 3.78(3H, s), 3.80-3.92(2H,m), 4.02(1H, d), 4.69(1H, t), 4.81-4.91(1H, m), 4.96(1H, d), 5.34(1H,d), 6.65(1H, d), 6.76(1H, brs), 7.07-7.13(2H, m), 7.25-7.75(8H, m),7.74(1H, d), 8.18(1H, s)

MS(FAB)m/z: 515(MH⁺)

Example 9

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclopropylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclopropylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that cyclopropylcarbonylchloride was used instead of pivaloyl chloride, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 0.52-0.77(2H, m), 0.88-1.00(1H, m), 1.03-1.19(2H, m),1.41(9H, s), 3.82-3.95(1H, m), 4.43-4.65(2H, m), 5.52(1H, brd),7.17-7.39(4H, m), 8.38(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclopropylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-cyclopropylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.58-0.75(2H, m), 0.90-1.03(1H, m), 1.13-1.35(2H, m),1.41(9H, s), 2.49(3H, s), 3.88(1H, dd), 4.46(1H, t), 4.50(1H, d),4.58-4.69(1H, m), 5.11(2H, ABq), 7.22-7.45(7H, m), 7.74(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclopropylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclopropylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 207-209° C.

¹H-NMR(CDCl₃) δ: 0.57-0.78(2H, m), 0.95-1.04(1H, m), 1.12-1.36(2H, m),2.26(3H, s), 2.42(3H, s), 3.91(1H, dd), 4.57(1H, t), 4.85-4.98(1H, m),5.12(2H, s), 6.12(1H, d), 6.82(1H, d), 6.98-7.46(11H, m), 7.70(1H, d)

MS(FAB)m/z: 511(MH⁺)

Example 10

Preparation of3-[3-(1-tert-butylcarbonylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except thatbromomethyl-tert-butylketone was used instead of2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.01(9H, s), 1.28(9H, s), 1.39(9H, s), 3.95(1H, dd),4.05(1H, d), 4.21(1H, t), 4.43-4.53(1H, m), 5.23(1H, d), 5.49(1H, d),7.08-7.43(4H, m)

Step 2

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-tert-Butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1 g) was dissolved in chloroform (10 ml), 4N HCl-dioxane (5 ml) wasadded to the solution, and the mixture was stirred at 50° C. for onehour. After the reaction mixture was allowed to cool, crystals soprecipitated were collected by filtration. The crystals were neutralizedwith saturated aqueous sodium bicarbonate, and extracted with methylenechloride, dried over anhydrous sodium sulfate, to thereby obtain 720 mgof the titled compound (Yield: 92%).

Step 3

Preparation of1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (340 mg) was dissolved in anhydroustetrahydrofuran (50 ml), triphosgene (228 mg) was added, triethylamine(0.9 ml) was added thereto five times after divided into five portionsover 15 minutes at 0° C., and the mixture was stirred at roomtemperature for 5 minutes. To this solution was added a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinethat obtained from Step 2 in tetrahydrofuran (10 ml), the resultantmixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure, water was added, andthe mixture was extracted with methylene chloride. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 870 mg of the titled compound (Yield:79%).

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 1.26(9H, s), 1.34(3H, t), 3.94(1H, dd),4.09(1H, d), 4.32(2H, q), 4.36(1H, t), 4.77-4.88(1H, m), 5.32(1H, d),6.29(1H, d), 7.11-7.52(7H, m), 7.61(1H, d), 7.92(1H, s)

Step 4

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea(500 mg) was dissolved in methanol (20 ml), the solution of lithiumhydroxide monohydrate (191 mg) in water (10 ml) was added, the mixturewas stirred at 50° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure, after acidification with 1N hydrochloric acid,the mixture was extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate, and recrystallized from ethanol andisopropyl ether, to thereby obtain 380 mg of the titled compound (Yield:73%).

Melting point: 231-233° C.

¹H-NMR(CDCl₃) δ: 1.06(9H, s), 1.29(9H, s), 4.06-4.18(2H, m), 4.39(1H,t), 4.67-4.78(1H, m), 5.23(1H, d), 7.13-8.32(11H, m)

MS(FAB)m/z: 523(MH⁺)

Example 11

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(4-chlorophenyl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(4-chlorophenyl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that 4-chlorobenzoyl chloridewas used instead of pivaloyl chloride, to thereby obtain the titlecompound.

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 4.16-4.23(1H, m), 4.35-4.49(1H, m),4.62-4.76(1H, m), 5.54(1H, brd), 6.76-7.27(8H, m), 8.18(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(4-chlorophenyl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(4-chlorophenyl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.55(3H, s), 4.20(1H, dd), 4.25-4.45(1H,m), 4.64-4.79(1H, m), 4.95(1H, d), 5.39(1H, d), 5.59(1H, d),6.72-7.50(11H, m), 7.81(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(4-chlorophenyl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(4-chlorophenyl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 212-214° C.

¹H-NMR(CDCl₃) δ: 2.21(3H, s), 2.47(3H, s), 4.20(1H, dd), 4.40-4.58(1H,m), 4.90-5.10(2H, m), 5.29(1H, d), 6.26(1H, d), 6.79(1H, d),6.95-7.50(19H, m), 7.77(1H, d)

MS(FAB)m/z: 581(MH⁺)

Example 12

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-acetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-acetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that acetyl chloride was usedinstead of pivaloyl chloride, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 1.80(3H, s), 3.78-3.91(1H, m),4.43-4.68(2H, m), 5.49(1H, brs), 7.10-7.44(4H, m), 8.05(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-acetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-acetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.90(3H, s), 2.46(3H, s), 3.84(1H, dt),4.59(2H, d), 5.12(2H, q), 5.49(1H, d), 7.72-7.46(7H, m), 7.72(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-acetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-acetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 215-217° C.

¹H-NMR(CDCl₃) δ: 1.94(3H, s), 2.25(3H, s), 2.35(3H, s), 4.37(1H, dd),4.72(1H, t), 4.82-4.97(2H, m), 5.38(1H, d), 6.33(1H, d), 6.79(1H, d),7.06-7.69(12H, m)

MS(FAB)m/z: 485(MH⁺)

Example 13

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Step 3 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 3 of Example 4 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 1.35(3H, t), 2.39(3H, s), 2.49(3H, s),3.96(1H, dd), 4.29-4.42(4H, m), 4.80-4.87(1H, m), 5.49(1H, d), 6.26(1H,d), 7.04-7.94(12H, m)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 246-248° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.08(9H, s), 2.39(3H, s), 2.56(3H, s), 4.11(1H, dd),4.43(1H, dd), 4.58(1H, d), 4.76-4.86(1H, m), 5.48(1H, d), 7.06-7.74(11H,m), 8.18(1H, s), 8.35(1H, d), 10.50(1H, br)

MS(FAB)m/z: 571(MH)⁺

Step 3

Preparation of(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineand(−)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(5.60 g) that obtained from Step 3 of Example 4 was dissolved in ethylacetate (150 ml), (+)-dibenzoyl-D-tartaric acid monohydrate (4.43 g) wasadded, and the mixture was stirred at room temperature. Crystals soprecipitated were collected by filtration, and washed with ethylacetate, to thereby obtain the dibenzoyl tartaric acid salt (4.24 g,Melting point: 167-168° C.). The filtrate and the washings were storedelsewhere. The salt was suspended in saturated aqueous sodiumbicarbonate, the mixture was extracted with chloroform. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure, tothereby obtain(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Optical purity: 99%ee (the ee value was determined by High PerformanceLiquid Chromatography).

[α] D²⁵ (C=1, MeOH): +45.2°

The above filtrate and the washings were concentrated under reducedpressure, the residue was dissolved in chloroform, and successivelywashed with saturated aqueous sodium bicarbonate, water, and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, the residue was dissolved in ethylacetate (80 ml), and the solution, after addition of(−)-dibenzoyl-L-tartaric acid monohydrate (2.45 g), was stirred at roomtemperature. White crystals so precipitated were collected byfiltration, washed with ethyl acetate, to thereby obtain the dibenzoyltartaric acid salt (4.26 g, Melting point: 166-167° C.). This salt wassuspended in saturated aqueous sodium bicarbonate, and the suspensionwas extracted with chloroform. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure, to thereby obtain(−)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Optical purity: 99%ee (the ee value was determined by High PerformanceLiquid Chromatography).

[α] D²⁵ (C=1, MeOH): −45.5°

Step 4

Preparation of(+)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Isophthalic acid monobenzyl ester (2.06 g) was dissolved in anhydrous1,4-dioxane (15 ml), diphenylphosphoryl azide (2.43 g) and triethylamine(0.97 g) were added, and the mixture was stirred at 75-80° C. for 2hours and 30 minutes. After allowed to cool, a solution of(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.18 g) that obtained from Step 3 in anhydrous 1,4-dioxane (10 ml) wasadded dropwise, and the mixture was stirred at room temperature for onehour. The reaction mixture was concentrated under reduced pressure. Theresidue, after addition of saturated aqueous sodium bicarbonate, wasextracted with chloroform. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 2.91 g of(+)-1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylpheny)urea(Yield: 82.6%) as white amorphous.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 2.38(3H, s), 2.46(3H, s), 3.94(1H, dd),4.31-4.40(2H, m), 4.82-4.86(1H, m), 5.31(2H, s), 5.39(1H, d), 6.41(1H,br), 7.02-7.41(12H, m), 7.57-7.66(3H, m), 7.74(1H, br), 7.95(1H, s)

The above compound was dissolved in methanol (50 ml) and tetrahydrofuran(10 ml), 10% palladium carbon (300 mg) was added, the mixture wasstirred under hydrogen atmosphere at room temperature for 2 hours. Thereaction mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was dissolved in ethyl acetate, isopropylether was added for crystallization, and crystals were collected byfiltration, to thereby obtain 2.05 g of the titled compound.

[α] D²⁵ (C=1, MeOH): +21.7°

Melting point: 160-161° C. (contraction)

Step 5

Preparation of(−)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 was repeated except that(−)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

[α] D²⁵ (C=1, MeOH): −20.2°

Melting point: 160-161° C. (contraction)

Example 14

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that cyclohexylcarbonyl chloridewas used instead of pivaloyl chloride, to thereby obtain the titlecompound.

¹H-NMR(CDCl₃) δ: 0.80-1.26(2H, m), 1.35-1.69(17H, m), 1.93-2.07(1H, m),3.78-3.85(1H, m), 4.46-4.63(2H, m), 5.42(1H, brd), 7.15-7.42(4H, m),7.89(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.84-1.89(19H, m), 2.05-2.22(1H, m), 2.50(3H, s),3.84(1H, dd), 4.54(1H, t), 4.55-4.65(1H, m), 4.82(1H, d), 5.30(1H, d),5.49(1H, d), 7.21-7.45(7H, m), 7.75(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 148-151° C.

¹H-NMR(CDCl₃) δ: 0.80-1.95(10H, m), 2.10-2.25(1H, m), 2.26(3H, s),2.43(3H, s), 3.87(1H, dd), 4.56(1H, t), 4.80-5.00(2H, m), 5.24(1H, d),6.13(1H, d), 6.81(1H, d), 7.00-7.50(11H, m), 7.68(1H, d)

MS(FAB)m/z: 553(MH⁺)

Example 15

Preparation of1-[1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Bromo-N-methyl-N-phenylacetamide (661 mg), 1N aqueous sodium hydroxide(10 ml) and tetra n-butylammonium bromide (77 mg) were added to asolution of2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(930 mg) that obtained from Referential Example 3 in toluene (25 ml),the mixture was stirred at room temperature for one hour. Water (125 ml)was added to the reaction mixture and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 1.09 g of the title compound (Yield:85.0%) as colorless oil.

¹H-NMR(CDCl₃) δ: 3.34(3H, s), 3.56(1H, dd), 3.79(1H, d), 4.21(1H, dd),4.57-4.72(2H, m), 5.07(2H, s), 5.91(1H, d), 6.69(2H, d), 6.81(1H, t),7.10-7.50(16H, m)

Step 2

Preparation of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

25% Hydrogen bromide solution in acetic acid (10 ml) was added to1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.10 g), the mixture was stirred at room temperature for one hour.Ether was added to the reaction mixture, crystals so precipitated werecollected by filtration. Water and saturated aqueous sodium bicarbonatewere added to the crystals, extracted with methylenechloride. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, tothereby obtain 710 mg of the title compound (Yield: 86.1%) as colorlessoil.

¹H-NMR(CDCl₃) δ: 1.68(2H, brs), 3.36(3H, s), 3.52(1H, dd), 3.64-3.82(2H,m), 3.94(1H, dd), 4.74(1H, d), 6.69(2H, d), 6.80(1H, t), 7.10-7.52(11H,m)

Step 3

Preparation of1-[1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea.1.5hydrate

1,1′-Carbonyldiimidazole (243 mg) was added to a solution of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(500 mg) in anhydrous methylene chloride (10 ml), the mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved inanhydrous tetrahydrofuran (15 ml), and the solution, after addition of3-(methylsulfonylaminocarbonyl)aniline (321 mg) and triethylamine (0.21ml), was refluxed overnight. The resultant mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography (chloroform:methanol=10:1), to thereby obtain 240 mg ofthe title compound as a white solid.

Melting point: 242-244° C. (decomposition)

¹H-NMR(DMSO-d₆, 100° C.) δ: 2.87(3H, s), 3.21(3H, s), 3.54(1H, dd),4.02(1H, dd), 4.23(1H, d), 4.49(1H, d), 4.50-4.64(1H, m), 6.44(1H, d),6.71-6.83(3H, m), 7.05-7.54(15H, m), 7.83(1H, t), 8.68(1H, brs)

IR(KBr)cm⁻:3346, 1653, 1593, 1549, 1497

MS(FAB)m/z: 641(MH)⁺

Example 16

Preparation of1-(1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere a solution of2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.94 g) that obtained from Referential Example 3 in anhydroustetrahydrofuran (30 ml) was added to a suspension of 60% sodium hydride(400 mg) in anhydrous tetrahydrofuran (30 ml) at 0° C., the mixture wasstirred at room temperature for one hour. Tert-butyl bromoacetate (1.46g) in anhydrous tetrahydrofuran (15 ml) to this solution, the resultantmixture was stirred at room temperature for one hour. Water (300 ml) wasadded to the reaction mixture, extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure.Isopropyl ether was added for trituration to the residue, filtered, tothereby obtain 1.74 g of the titled compound (Yield: 69.4%) as a whitesolid.

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 3.62(1H, dd), 4.11(1H, d), 4.18-4.28(1H,m), 4.57-4.70(2H, m), 5.08(2H, s), 5.89(1H, d), 6.74(2H, d), 6.86(1H,t), 7.14-7.38(11H, m)

Step 2

Preparation of1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

10% Palladium carbon (150 mg) was added to a suspension of1-tert-butoxycarbonylmethyl-2-oxo-3-benzytoxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.50 g) in methanol (50 ml), the mixture was stirred under hydrogenatmosphere at room temperature for 4 hours. The reaction mixture wasfiltered, the filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 920 mg of the titlecompound (Yield: 83.5%) as colorless oil.

¹H-NMR(CDCl₃) δ: 1.48(9H, s), 1.65(2H, brs), 3.52-3.63(1H, m),3.68-3.77(1H, m), 3.93-4.01(1H, m), 4.02(1H, d), 4.76(1H, d), 6.75(2H,d), 6.85(1H, t), 7.14-7.30(6H, m)

Step 3

Preparation of1-(1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.36(9H, s), 2.95(3H, s), 3.61(1H, dd), 4.01(1H, dd),4.48-4.73(3H, m), 6.60-6.92(4H, m), 7.13-7.58(10H, m), 7.81(1H, brs),8.96(1H, brs)

IR(KBr)cm⁻¹:3368, 1746, 1668, 1593

MS(FAB)m/z: 612(MH⁺)

Example 17

Preparation of1-[1-(2,2,2-trifluoro)ethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-(2,2,2-trifluoro)ethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere potassium carbonate (464 mg) and1-iodo-2,2,2-trifluoroethane (0.50 ml) were added to a suspension of2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(650 mg) that obtained from Referential Example 3 in anhydrousN,N-dimethylformamide (30 ml), the mixture was stirred internaltemperature at 85° C. overnight. Water was added to the reactionmixture, extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=2:1), tothereby obtain 374 mg of the title compound (Yield: 47.4%) as a whitesolid.

¹H-NMR(CDCl₃) δ: 3.63(1H, dd), 4.00-4.20(2H, m), 4.53-4.71(1H, m),4.88-5.10(3H, m), 5.79(1H, d), 6.76(2H, d), 6.90(1H, t), 7.03-7.40(11H,m)

MS(EI)m/z: 469(M⁺)

Step 2

Preparation of1-(2,2,2-trifluoro)ethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

10% Palladium carbon (48 mg) was added to a suspension of1-(2,2,2-trifluoro)ethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(480mg) in methanol (15 ml), the mixture was stirred under hydrogenatmosphere at 50° C. for 2 hours. The reaction mixture was filtrated,the filtrate was evaporated under reduced pressure, to thereby obtain334 mg of the title compound (Yield: 97.7%) as colorless oil.

Step 3

Preparation of1-[1-(2,2,2-trifluoro)ethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-(2,2,2-trifluoro)ethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 2.99(3H, s), 3.60-3.75(1H, m), 3.88-4.04(1H, m),4.47-4.68(2H, m), 4.96-5.18(1H, m), 6.63-6.90(4H, m), 7.08-7.56(9H, m),7.69-7.85(2H, m), 8.99(1H, brs)

MS(FAB)m/z: 576(MH)⁺

Example 18

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-(2-toluoylmethyl)-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 15 was repeated except that2-bromo-2′-methylacetophenone was used instead of2-bromo-N-methyl-N-phenylacetamide, to thereby obtain the titlecompound.

¹H-NMR(CDCl₃) δ: 2.51(3H, s), 3.64(1H, dd), 4.26(1H, dd), 4.65-4.75(1H,m), 4.80(1H, d), 5.09(2H, s), 5.36(1H, d), 5.91(1H, d), 6.74(2H, d),6.87(1H, t), 7.14-7.42(14H, m), 7.70(1H, d)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 17 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2,2,2-trifluoro)ethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 210-220° C.

¹H-NMR(DMSO-d₆) δ: 2.40(3H, s), 2.94(3H, s), 3.60(1H, dd), 4.04(1H, dd),4.58-4.63(1H, m), 5.17(1H, d), 5.38(1H, d), 6.68(1H, d), 6.77-6.98(3H,s), 7.15-7.58(13H, m), 7.83(1H, brs), 7.89(1H, d), 8.99(1H, s)

MS(FAB) m/z: 626(MH⁺)

Example 19

Preparation of1-(1-methoxymethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-methoxymethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinethat obtained from Step 7 of Referential Example 3 was used instead of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 199-205° C.

¹H-NMR(DMSO-d₆) δ: 2.91(3H, s), 3.16(3H, s), 3.66(1H, dd), 3.97(1H, dd),4.52-4.57(1H, m), 5.20(1H, d), 5.30(1H, d), 6.66(1H, d), 6.76-6.87(3H,m), 7.13-7.84(11H, m), 8.96(1H, brs)

MS(FAB)m/z: 576(M+K)⁺

Example 20

Preparation of1-[2-oxo-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-chloroacetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that chloroacetyl chloride wasused instead of pivaloyl chloride, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 3.77(2H, ABq), 3.90-3.96(1H, m),4.50-4.65(2H, m), 5.58(1H, brs), 7.16-7.52(4H, m), 8.16(1H, s)

Step 2

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-[4-(1-methyl)piperazino]methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

N-Methylpiperazine (612 mg), potassium carbonate (845 mg), and potassiumiodide (100 mg) were added to a solution of2-oxo-3-tert-butoxycarbonylamino-5-chloroacetyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.16 g) in acetone (100 ml), the mixture was refluxed for 3hours. Afterallowed to cool, the in soluble material was removed by filtration, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (silica gel NH-DM1020,produced by Fujisilicia Co. Ltd., chloroform:methanol=50:1), to therebyobtain 2.35 g of the title compound (Yield: 92%).

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 2.16-2.50(11H, m), 2.75(1H, d), 2.90(1H,d), 3.80-3.88(1H, m), 4.48-4.65(2H, m), 5.50(1H, d), 7.13-7.43(4H, m),8.29(1H, brs)

Step 3

Preparation of1-[2-oxo-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

¹H-NMR(DMSO-d₆) δ: 2.00-2.25(14H, m), 2.77(1H, s), 3.55-3.70(1H, m),4.38-4.50(2H, m), 6.62-6.75(2H, m), 7.04-7.55(8H, m), 8.70(1H, s),10.17(1H, s)

MS(FAB)m/z: 451(MH⁺)

Example 21

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinethat obtained from Step 2 of Example 20 was used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 2.27(3H, s), 2.32-2.65(11H, m), 2.97(2H,ABq), 3.78-3.90(1H, m), 4.51-4.63(2H, m), 5.10(2H, s), 5.49(1H, d),7.22-7.47(7H, m), 7.73(1H, d)

Step 2

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(4-methylpiperazin-1-yl)methylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 245-247° C.

¹H-NMR(CDCl₃) δ: 2.20(3H, s), 2.26(3H, s), 2.30-2.62(11H, m), 2.93(1H,d), 3.04(1H, d), 3.88(1H, dd), 4.70(1H, t), 4.84-4.92(1H, m), 4.95(1H,d), 5.17(1H, d), 6.21(1H, d), 6.82(1H, d), 7.00-7.67(11H, m), 7.67(1H,d)

MS(FAB)m/z: 583(MH⁺)

Example 22

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that benzoyl chloride was usedinstead of pivaloyl chloride, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 4.17(1H, dd), 4.43(1H, t), 4.63-4.73(1H,m), 5.55(1H, brd), 6.70-7.27(9H, m), 8.16(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.57(3H, s), 4.21-4.49(2H, m),4.70-4.90(2H, m), 5.47-5.69(2H, m), 6.76-7.54(12H, m), 7.83(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 2.19(3H, s), 2.50(3H, s), 4.21(1H, dd), 4.42-4.60(1H,m), 4.92(1H, d), 4.92-5.10(1H, m), 5.43(1H, d), 6.34(1H, d),6.74-6.85(2H, m), 6.90-7.08(4H, m), 7.10-7.45(11H, m), 7.79(1H, d)

MS(FAB)m/z: 547(MH⁺)

Example 23

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinethat obtained from Step 2 of Example 22 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Step 2

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 2.45(3H, s), 2.92(3H, m), 3.85-4.05(1H, m),4.20-4.40(1H, m), 4.65-4.72(1H, m), 5.20(1H, d), 5.53(1H, d), 6.75(1H,d), 6.85-7.58(16H, m), 7.83(1H, s), 8.03(1H, d), 8.93(1H, s)

MS(FAB)m/z: 654(MH⁺)

Example 24

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(832 mg) was dissolved in methanol (20 ml), sodium bicarbonate (445 mg)and benzyl bromide (906 mg) were added, the mixture was stirredovernight. The reaction mixture was concentrated under reduced pressure,the residue, after addition of water, was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate, the solvent wasconcentrated under reduced pressure, the crystals were washed withisopropyl ether, to thereby obtain 980 mg of the titled compound (Yield:86.9%).

¹H-NMR(CDCl₃) δ: 1.37(9H, s), 3.21(1H, t), 3.45-3.52(1H, m), 4.09(1H,d), 4.44(1H, d), 4.45-4.58(1H, m), 5.44(1H, brd), 6.98-7.31(9H, m),7.68(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.37(9H, s), 2.54(3H, s), 3.21(1H, t), 3.43(1H, t),4.05(1H, d), 4.40(1H, d), 4.49-4.54(1H, m), 4.71(1H, d), 5.44(1H, d),5.48(1H, brs), 7.03-7.43(12H, m), 7.74(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 169-172° C.

¹H-NMR(CDCl₃) δ: 2.22(3H, s), 2.48(3H, s), 3.18(1H, dd), 3.50(1H, dd),4.02(1H, d), 4.38(1H, d), 4.73-4.90(2H, m), 5.37(1H, d), 6.06(1H, d),6.75-7.40(17H, m), 7.66(1H, d)

MS(FAB)m/z: 533(MH⁺)

Example 25

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinethat obtained from Step 2 of Example 24 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Step 2

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 2.45(3H, s), 3.03(3H, s), 3.07-3.15(1H, m),3.30-3.36(1H, m), 4.16(1H, d), 4.39(1H, d), 4.44-4.59(1H, m), 4.99(1H,d), 5.39(1H, d), 6.56(1H, d), 7.14-7.51(16H, m), 7.78(1H, s), 7.92(1H,d), 8.78(1H, s)

MS(FAB)m/z: 640(MH⁺)

Example 26

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(N-cyclohexylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(N-cyclohexylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Cyclohexyl isocyanate (363 mg) was added to a solution of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(800 mg) in tetrahydrofuran (50 ml), the mixture was refluxed for 2days. The reaction mixture was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1), to thereby obtain 790 mg of the title compound (Yield:68%).

¹H-NMR(CDCl₃) δ: 0.80-2.02(19H, m), 3.51-3.73(1H, m), 3.80-4.07(2H, m),4.33-4.55(2H, m), 5.43(1H, brd), 7.15-7.37(4H, m), 7.90(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(N-cyclohexylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(N-cyclohexylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.95-1.76(17H, m ), 1.81-1.99(2H, m), 2.42(3H, s),3.57-3.77(1H, m), 3.90(1H, dd), 4.27(1H, t), 4.49-4.61(1H, m), 4.65(1H,d), 5.02(1H, d), 5.39-5.49(2H, m), 7.20-7.44(7H, m), 7.75(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(N-cyclohexylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(N-cyclohexylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 117-119° C.

¹H-NMR(CDCl₃) δ: 0.96-1.67(8H, m), 1.82-1.96(2H, m), 2.27(3H, s),2.37(3H, s), 3.60-3.75(1H, m), 3.94(1H, dd), 4.36(1H, t), 4.80-4.90(2H,m), 4.96(1H, d), 5.54(1H, d), 6.27(1H, d), 6.81(1H, brs), 7.04-7.44(10H,m), 7.64(1H, s), 7.69(1H, d)

MS(FAB)m/z: 568(MH⁺)

Example 27

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(N,N-dimethylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(N,N-dimethylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that N,N-dimethylcarbamoylchloride was used instead of pivaloyl chloride, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 2.52(6H, s), 3.69(1H, t), 4.17(1H, dd),4.47-4.58(1H, m), 5.38(1H, d), 7.08-7.13(2H, m), 7.22-7.29(2H, m),7.90(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(N,N-dimethylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(N,N-dimethyl)carbamoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 2.54(3H, s), 2.59(6H, s), 3.62-3.71(1H,m), 4.17-4.24(1H, m), 4.55-4.66(2H, m), 5.38-5.48(2H, m), 7.08-7.46(7H,m), 7.75(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(N,N-dimethylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(N,N-dimethylcarbamoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 199-201° C.

¹H-NMR(CDCl₃) δ: 2.21(3H, s), 2.50(3H, s), 2.61(6H, s), 3.79(1H, t),4.19(1H, dd), 4.68(1H, d), 4.88-4.96(1H, m), 5.43(1H, d), 6.24(1H, d),6.71-7.76(13H, m)

MS(FAB)m/z: 514(MH⁺)

Example 28

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclopentylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that cyclopentylcarbonylchloride was used instead of pivaloyl chloride, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 1.24-1.47(11H, m), 1.53-1.78(5H, m), 1.82-1.97(1H, m),2.32-2.43(1H, m), 3.80-3.87(1H, m), 4.50-4.66(2H, m), 5.42(1H, brd),7.14-7.41(4H, m), 7.72(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.26-1.98(17H, m), 2.44-2.59(4H, m), 3.77-3.92(1H, m),4.55-4.66(2H, m), 4.87(1H, d), 5.24(1H, d), 5.50(1H, d), 7.22-7.45(7H,m), 7.74(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclopentylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 186-188° C.

¹H-NMR(CDCl₃) δ: 1.28-1.56(2H, m), 1.58-2.94(6H, m), 2.26(3H, s),2.44(3H, s), 2.54(1H, t), 3.88(1H, dd), 4.63(1H, t), 4.84-4.95(1H, m),4.96(1H, d), 5.18(1H, d), 6.19(1H, d), 6.81(1H, d), 7.02-7.48(11H, m),7.68(1H, d)

MS(FAB)m/z: 539(MH⁺)

Example 29

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that isobutyryl chloride wasused instead of pivaloyl chloride, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.87(3H, d), 1.08(3H, d), 1.41(9H, s), 2.32(1H, q),3.78-3.87(1H, m), 4.47-4.70(2H, m), 5.43(1H, d), 7.13-7.45(4H, m),7.62(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.99(3H, d), 1.13(3H, d), 2.46(1H, q), 2.52(3H, s),3.86(1H, dd), 4.26-4.64(2H, m), 4.74(1H, d), 5.35(1H, d), 5.51(1H, d),7.23-7.49(7H, m), 7.74(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example l, to therebyobtain the title compound.

Melting point: 174.5-175.5° C.

¹H-NMR(CDCl₃) δ: 1.03(3H, d), 1.15(3H, d), 2.26(3H, s), 2.42-2.54(4H,m), 3.90(1H, dd), 4.63(1H, dd), 4.79(1H, d), 4.81-4.95(1H, m), 5.31(1H,d), 6.14(1H, d), 6.82(1H, d), 7.00-7.45(11H, m), 7.67(1H, d)

MS(FAB)m/z: 513(MH⁺)

Example 30

Preparation of3-[3-[1-[N-phenyl-N-(2-hydroxyethyl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[N-phenyl-N-(2-benzyloxyethyl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-bromo-[N-phenyl-N-(2-benzyloxyethyl)acetamide was used instead of2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.89(9H, s), 1.39(9H, s), 3.53-3.97(5H, m),4.09-4.31(2H, m), 4.42-4.70(4H, m), 5.54(1H, d), 7.14-7.49(14H, m)

Step 2

Preparation of1-[1-[N-phenyl-N-(2-benzyloxyethyl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-[N-phenyl-N-(2-benzyloxyethyl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 0.92(9H, s), 1.33(3H, t), 3.50-3.77(4H, m), 3.9(11H,dd), 4.16-4.48(6H, m), 4.68-4.87(2H, m), 6.41(1H, d), 7.16-7.60(18H, m),7.95(1H, s)

Step 3

Preparation of3-[3-[1-[N-phenyl-N-(2-benzyloxyethyl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-[N-Phenyl-N-(2-benzyloxyethyl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(1.01 g) was dissolved in methanol (30 ml), lithium hydroxide (294 mg)in water (30 ml) was added, the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,acidified with 1N hydrochloric acid, and crystals so precipitated werecollected by filtration, to thereby obtain 770 mg of the title compound(Yield: 79%).

¹H-NMR(CDCl₃) δ: 0.94(9H, s), 3.64-3.72(3H, m), 3.83-3.92(1H, m),4.06-4.20(2H, m), 4.34(1H, t), 4.45-4.72(4H, m), 7.22-7.73(18H, m),8.21(1H, s), 8.33(1H, d), 10.50(1H, brs)

Step 4

Preparation of3-[3-[1-[N-phenyl-N-(2-hydroxyethyl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

3-[3-[1-[N-Phenyl-N-(2-benzyloxyethyl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid (770 mg) was dissolved in ethanol (50 ml), 10% Palladium carbon(100 mg) was added, under hydrogen atmosphere the mixture was stirred at50° C. for 2 hours. The reaction mixture was filtrated, the filtrate wasevaporated under reduced pressure, to thereby obtain 580 mg of the titlecompound (Yield: 87%).

¹H-NMR(CDCl₃) δ: 0.95(9H, s), 3.71-4.12(7H, m), 4.30-4.79(3H, m),7.03(1H, d), 7.21-7.75(13H, m), 8.10(2H, brs)

MS(FAB)m/z: 602(MH⁺)

Example 31

Preparation of3-[3-[1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

Step 1

Preparation of1-[N-(1-benzylpiperidin-4-yl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-bromo-N-(1-benzylpiperidin-4-yl)acetamide was used instead of2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.97(9H, s), 1.42(9H, s), 1.44-1.59(2H, m),1.91-1.97(2H, m), 2.05-2.19(2H, m) 2.74-2.83(2H, m), 3.48(2H, s),3.76(1H, d), 3.77-3.89(2H, m), 4.25-4.46(2H, m), 4.92(1H, d), 5.35(1H,d), 6.35(1H, d), 7.18-7.49(9H, m)

Step 2

Preparation of1-[N-(piperidin-4-yl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Ammonium formate (1.92 g) and 10% palladium carbon (300 mg) was added toa solution of1-[N-(1-benzylpiperidin-4-yl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.0 g) in etanol (100 ml), the mixture was refluxed for 5 hours. Thereaction mixture was filtrated, the filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (chloroform:methanol=30:1), to thereby obtain 1.1 g ofthe title compound (Yield: 62%).

¹H-NMR(CDCl₃) δ: 0.98(9H, s), 1.31-1.44(11H, m), 1.59(1H, brs),1.86-2.00(2H, m), 2.63-2.74(2H, m), 3.01-3.12(2H, m), 3.76-3.93(3H, m),4.32(1H, t), 4.39-4.73(11H, m), 4.91(1H, d), 5.42(1H, d), 6.37(1H, d),7.21-7.35(2H, m), 7.42-7.52(2H, m)

Step 3

Preparation of1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-N-(Piperidin-4-yl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) was dissolved in the mixed solvent (100 ml) of acetonitrile andmethanol (1:1), 37% formalin (2ml) and sodium cyanoborohydride (377 mg)was added, and acetic acid (l ml) was added thereto dropwise, themixture was stirred at 50° C. for one hour. After the reaction mixturewas concentrated under reduced pressure, water was added to the residue,and extracted with chloroform. The organic layer was washed withsaturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate, and purified by silica gel column chromatography (chloroform),to thereby obtain 640 mg of the title compound (Yield: 52%).

¹H-NMR(CDCl₃) δ: 0.98(9H, s), 1.41(9H, s), 1.43-1.58(2H, m),1.84-1.97(2H, m), 2.03-2.16(2H, m), 2.26(3H, s), 2.66-2.78(2H, m),3.78(1H, d), 3.79-3.88(2H, m), 4.30(1H, t), 4.38-4.57(1H, m), 4.89(1H,d), 5.41(1H, d), 6.32(1H, d), 7.19-7.35(2H, m), 7.41-7.55(2H, m)

Step 4

Preparation of1-[1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)ureahydrochloride

Step 2 of Example 10 was repeated except that1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of 1-tertbutylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.

Diphenylphosphoryl azide (391 mg) and triethylamine (152 mg) were addedto a solution of isophthalic acid monobenzylester (364 mg) in dioxane(50 ml), the mixture was stirred at 80° C. until bubbling was finished.After the reaction mixture was allowed to cool, a solution of1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(490 mg) in dioxane (10 ml) was added and then stirred at roomtemperature for 30 minutes. The resultant mixture was concentrated underreduced pressure, methylene chloride was added to the residue, andwashed with saturated aqueous sodium bicarbonate and saturated brine.After dried over anhydrous sodiun sulfate, the solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography (chloroform:methanol=5:1), and 4N HCl-dioxane was addedto the residue in a manner known per se in the art, to thereby obtain300 mg of the title compound.

¹H-NMR(CDCl₃) δ: 1.01(9H, s), 1.45-2.19(6H, m), 2.26(3H, s),2.73-2.85(2H, m), 3.75-3.90(2H, m), 3.93(1H, dd), 4.39(1H, t),4.68-4.75(1H, m), 5.07(1H, d), 5.33(2H, s), 6.28(1H, d), 7.07(1H, d),7.24-7.95(13H, m), 8.31(1H, s)

Step 5

Preparation of3-[3-[1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

10% Palladium carbon (100 mg) was added to a solution of1-[1-[N-(1-methylpiperidin-4-yl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)ureahydrochloride (300 mg) in ethanol (50 ml), under hydrogen atmosphere themixture was stirred at 50° C. for one hour. The reaction mixture wasfiltrated, the filtrate was evaporated under reduced pressure. Ethanolwas added to the residue, crystals so precipitated were collected byfiltration, to thereby obtain the title compound (Yield: 92%).

¹H-NMR(DMSO-d₆) δ: 0.92(9H, s), 1.65-2.05(4H, m), 2.70(3H, s),2.91-3.52(4H, m), 3.66(1H, dd), 3.73-4.03(2H, m), 4.22(1H, t),4.35-4.49(1H, m), 4.67(1H, d), 6.73(1H, d), 7.27-7.61(7H, m), 7.99(1H,t), 8.34(1H, d), 9.16(1H, s), 10.40(1H, brs), 12.50(1H, brs)

MS(FAB)m/z: 579(MH⁺)

Example 32

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 252-255° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.26(9H, s), 2.24(3H, s), 3.95(1H, dd),4.31(1H, t), 4.08(1H, d), 4.70-4.87(1H, m), 5.27(1H, d), 6.10(1H, d),6.73-6.82(2H, m), 6.92-7.18(4H, m), 7.22-7.48(3H, m)

MS(FAB)m/z: 493(MH)⁺

Example 33

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)]ureido]phenylthioaceticacid

Step 1

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 15 was repeated except thatbromomethyl-tert-butylketone was used instead of2-bromo-N-methyl-N-phenylacetamide, to thereby obtain1-tert-butylcarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.

¹H-NMR(CDCl₃) δ: 1.26(9H, s), 3.62(1H, dd), 4.14-4.43(2H, m),4.56-4.74(1H, m), 5.07(2H, s), 5.14(1H, d), 5.80-5.95(1H, m), 6.77(2H,d), 6.86(1H, t), 7.06-7.46(11H, m)

In a similar manner to Step 2 of Example 17, the title compound wasobtained.

¹H-NMR(CDCl₃) δ: 1.28(9H, s), 1.67(2H, brs), 3.57(1H, dd), 3.77(1H, dd),3.98(1H, dd), 4.19(1H, d), 5.26(1H, d), 6.77(2H, d), 6.85(1H, t),7.05-7.30(6H, m)

Step 2

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea

Triphosgene (138 mg) was added under ice-cooling to a solution of ethyl3-aminophenylthioacetate (262 mg) in tetrahydrofuran (50 ml),triethylamine (0.55 ml) was added five times each 0.11 ml over 15minutes. After the reaction mixture was stirred at room temperature for5 minutes, a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(500 mg) in tetrahydrofuran (10 ml) was added thereto, stirred at roomtemperature for one hour. Water was added to the reaction mixture,extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodiun sulfate, the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 330 mg of the title compound.

¹H-NMR(CDCl₃) δ: 1.20(3H, t), 1.24(9H, s), 3.62(2H, s), 3.65-3.76(1H,m), 4.14(2H, q), 4.15-4.21(1H, m), 4.45(1H, d), 4.84-4.95(1H, m),5.11(1H, d), 6.29(1H, d), 6.76-6.87(3H, m), 6.96-7.45(11H, m)

Step 3

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylthioaceticacid

A solution of lithium hydroxide monohydrate (104 mg) in water (5 ml) wasadded to a solution of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea(290 mg) in methanol (10 ml), the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure. Water was added and acidified with 1N hydrochloric acid.Crystals so precipitated were collected by filtration, to thereby obtain260 mg of the title compound (Yield: 94%).

¹H-NMR(CDCl₃) δ: 1.24(9H, s), 3.62(2H, s), 3.70(1H, dd), 4.16(1H, dd),4.43(1H, d), 4.85-4.93(1H, m), 5.10(1H, d), 5.50(1H, brs), 6.65(1H, d),6.75-7.33(13H, m), 7.39(1H, s)

MS(FAB)m/z: 561(MH⁺)

Example 34

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylsulfinylaceticacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylsulfinylphenyl)urea

1-(1-tert-Butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea(460 mg) obtained from Step 2 of Example 33 was dissolved in methylenechloride (20 ml), m-chloroperbenzoic acid (170mg) was added underice-cooling, stirred for 30 minutes. The reaction mixture was washedsubsequently with saturated aqueous sodium bicarbonate and saturatedbrine, dried over anhydrous sodiun sulfate, and the residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:2), tothereby obtain 320 mg of the title compound (Yield: 68%).

¹H-NMR(CDCl₃) δ: 1.58 and 1.70(3H, each t), 1.25(9H, s), 3.70-3.89(3H,m), 4.10(1H, q), 4.1(1H, q), 4.15-4.23(1H, m), 4.45(1H, dd),4.83-4.94(1H, m), 5.16(1H, d), 6.65-6.88(4H, m), 7.13-7.35(8H, m),7.54-7.59(1H, m), 7.67-7.73(1H, m), 7.90(1H, d)

Step 2

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylsulfinylaceticacid

Step 3 of Example 33 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylsulfinylphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea,to thereby obtain the title compound.

¹H-NMR(DMSO-d6) δ: 1.17(9H, s), 3.54-3.79(3H, m), 3.96-4.05(1H, m),4.53-4.63(1H, m), 4.75(1H, d), 5.11(1H, d), 6.77-6.89(4H, m),7.11-7.49(10H, m), 7.77(1H, s), 9.29(1H, s)

MS(FAB)m/z: 599(MH⁺)

Example 35

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenoxyaceticacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmetoxyphenyl)urea

Step 2 of Example 33 was repeated except that ethyl3-aminophenoxyacetate was used instead of ethyl3-aminophenylthioacetate, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.24(9H, s), 1.27(3H, t), 3.67(1H, dd), 4.18-4.23(1H,m), 4.24(2H, q), 4.42(1H, d), 4.55(2H, s), 4.83-4.91(1H, m), 5.12(1H,d), 6.23(1H, d), 6.57(1H, dd), 6.76-6.92(5H, m), 7.03-7.23(8H, m)

Step 2

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenoxyaceticacid

Step 3 of Example 33 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethoxyphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea,to thereby obtain title compound.

¹H-NMR(CDCl₃) δ: 1.22(9H, s), 3.67(1H, dd), 4.29(1H, dd), 4.35(1H, d),4.62(2H, s), 4.85-4.94(1H, m), 5.14(1H, d), 6.45-6.94(6H, m),7.11-7.24(8H, m), 7.39-7.45(1H, m), 7.57(1H, s)

MS(FAB) m/z: 545(MH⁺)

Example 36

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylaminophenyl)urea

3-(N-tert-Butoxycarbonyl-N-methylamino)phenylisocyanate (209 mg) wasadded to a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin(350 mg) obtained from Step 1 of Example 33 in methylene chloride (l0ml)under ice-cooling, stirred at room temperature for 30 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was recrystallized from the mixed solvent of n-hexane and ethylacetate, to thereby obtain1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-N-tert-butoxycarbonyl-N-methylaminophenyl)urea.

This compound was dissolved in methylene chloride (10 ml),trifluoroacetic acid (5 ml) was added, and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was concentratedunder reduced pressure, saturated aqueous sodium bicarbonate was addedto the residue, and extracted with methylene chloride. The organic layerwas washed with saturated brine, dried over anhydrous sodiunsulfate, andthe residue was recrystallized from ethanol, to thereby obtain 300 mg ofthe title compound (Yield: 73%).

Melting point: 224-225° C.

¹H-NMR(CDCl₃) δ: 1.22(9H, s), 2.77(3H, s), 3.64(1H, dd), 3.70(1H, brs),4.25(1H, dd), 4.41(1H, d), 4.83-4.92(1H, m), 5.08(1H, d), 6.20-6.30(2H,m), 6.43-6.49(1H, m), 6.67-7.25(12H, m)

MS(FAB)m/z: 522(M+Na)⁺

Example 37

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 2 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 1 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.In a similar manner to Step 3 of Example 10 and subsequently Step 4 ofExample 10, the title compound was obtained.

¹H-NMR(CDCl₃) δ: 1.08(9H, s), 2.55(3H, s), 4.16(1H, dd), 4.44(1H, t),4.59(1H, d), 4.75-4.87(1H, m), 5.51(1H, d), 7.24-7.59(11H, m),7.66-7.75(2H, m), 8.16-8.37(2H, m)

MS(FAB)m/z: 557(MH)⁺

Example 38

Preparation of1-(1-phenyl-2-oxo-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 1

Preparation of1-phenyl-2-oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.38 g) was dissolved in N,N-dimethylformamide (20 ml), iodobenzene(1.36 g), copper powder (286 mg), copper iodide (446 mg) and potassiumcarbonate (622 mg) were added, the mixture was stirred at 150° C. for 2hours. The insoluble material was removed by filtration, the filtratewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=2:1), tothereby obtain 1.00 g of the title compound.

¹H-NMR(CDCl₃) δ: 3.43-3.52(2H, m), 3.99-4.10(1H, m), 4.73-4.83(1H, m),5.08(2H, s), 5.88(1H, d), 6.80-7.39(14H, m)

Step 2

Preparation of1-phenyl-2-oxo-3-benzyloxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-Phenyl-2-oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(300 mg) was dissolved in methylene chloride (15 ml), isobutyrylchloride (107 mg), pyridine (79 mg) and 4-(N,N-dimethyl)aminopyridine (1mg) were added, the mixture was refluxed for 2 hours. The reactionmixture was washed with 1N hydrochloric acid, saturated aqueous sodiumbicarbonate and saturated brine, dried over anhydrous sodium sulfate.The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 300 mg of the titlecompound (Yield: 85%).

¹H-NMR(CDCl₃) δ: 1.08(3H, d), 1.19(3H, d), 2.57(1H, q), 3.85(1H, dd),4.55(1H, t), 4.63-4.72(1H, m), 5.08(2H, s), 5.78(1H, d), 6.98-7.42(14H,m)

Step 3

Preparation of1-(1-phenyl-2-oxo-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

10% Palladium carbon (30 mg) was added to a solution of1-phenyl-2-oxo-3-benzyloxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(290 mg) in ethanol (20 ml), under hydrogen atmosphere the mixture wasstirred for 2 hours. The reaction mixture was filtrated, the filtratewas concentrated under reduced pressure. The residue was dissolved intetrahydrofuran (20 ml), m-tolyl isocyanate (85 mg) was added to thesolution, and then stirred at room temperature for 30 minutes. Theresultant mixture was concentrated under reduced pressure, the residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=1:1), to thereby obtain 150 mg of the title compound (Yield:52%).

¹H-NMR(CDCl₃) δ: 1.07(3H, d), 1.20(3H, d), 2.28(3H, s), 2.54-2.63(1H,m), 3.88(1H, dd), 4.64(1H, t), 4.95-5.02(1H, m), 6.06(1H, d),6.80-7.42(14H, m)

MS(FAB)m/z: 457(MH⁺)

Example 39

Preparation of1-(1-phenyl-2-oxo-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 1

Preparation of1-phenyl-2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 38 was repeated except that cyclohexylcarbonylchloride was used instead of isobutyryl chloride, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 0.95-1.30(2H, m), 1.43-1.88(8H, m), 2.16-2.28(1H, m),3.83(1H, dd), 4.53(1H, t), 4.60-4.74(1H, m), 5.08(2H, s), 5.77(1H, d),7.01-7.41(14H, m)

Step 2

Preparation of1-(1-phenyl-2-oxo-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 3 of Example 38 was repeated except that1-phenyl-2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-phenyl-2-oxo-3-benzyloxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 165-168° C.

¹H-NMR(DMSO-d₆) δ: 0.95-1.95(10H, m), 2.10-2.23(1H, m), 2.30(3H, s),3.62(1H, dd), 4.40-4.70(2H, m), 6.72(1H, d), 6.78(1H, d), 7.00-7.60(12H,m), 8.68(1H, s)

MS(FAB)m/z: 497(MH⁺)

Example 40

Preparation of1-[1-(N-tert-butylcarbamoylmethyl)-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-(N-tert-butylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 15 was repeated except thatN-tert-butyl-2-iodoacetamide was used instead of2-bromo-N-methyl-N-phenylacetamide, subsequently in a similar manner toStep 2 of Example 15, the title compound was obtained.

¹H-NMR(CDCl₃) δ: 1.07(9H, s), 1.67(2H, brs), 3.52-3.75(2H, m), 3.95(1H,dd), 4.24(1H, d), 4.54(1H, d), 6.16(1H, brs), 6.81(2H, d), 6.90(1H, t),7.17-7.41(6H, m)

Step 2

Preparation of1-[1-(N-tert-butylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-(N-tert-butylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.20(9H, s), 2.87(3H, s), 3.25-3.66(1H, m),3.93-4.05(1H, m), 4.19(1H, d), 4.49(1H, d), 4.50-4.65(1H, m), 6.64(1H,d), 6.76-6.88(3H, m), 7.12-7.58(11H, m), 7.78(1H, brs), 8.94(1H, brs)

IR(KBr)cm⁻¹:3346, 2969

MS(FAB)m/z: 607(MH)⁺

Example 41

Preparation of1-[1-(2,2-diethoxyethyl)-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of1-(2,2-diethoxyethyl)-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere,2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(930 mg) in anhydrous N,N-dimethylformamide (20 ml) was added to asuspension of 60% sodium hydride (192 mg) in anhydrousN,N-dimethylformamide (20 ml), then stirred at room temperature for onehour. After bromoacetaldehyde diethylacetal (946 mg) in anhydrousN,N-dimethylformamide (10 ml) was added to the mixture, the resultantmixture was stirred overnight internal temperature at 70-75° C.Ice-water was added to the reaction mixture, extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1), to thereby obtain 468 mg of the titlecompound as a white solid.

¹H-NMR(CDCl₃) δ: 1.06(3H, t), 1.14(3H, t), 3.40-4.20(8H, m),4.47-4.62(1H, m), 4.80(1H, t), 5.08(2H, s), 5.84(1H, d), 6.74(2H, d),6.85(1H, t), 7.10-7.40(10H, m), 7.56(1H, d)

Step 2

Preparation of1-(2,2-diethoxyethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 16 was repeated except that1-(2,2-diethoxyethyl)-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.06(3H, t), 1.16(3H, t), 3.40-4.00(9H, m), 4.83(1H,t), 6.77(2H, d), 6.84(1H, t), 7.10-7.40(7H, m), 7.55(1H, d)

Step 3

Preparation of1-[1-(2,2-diethoxyethyl)-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-(2,2-diethoxyethyl)-2-oxo-3-amino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 0.91(3H, t), 0.98(3H, t), 3.00(3H, s), 3.20-3.67(5H,m), 3.80(1H, dd), 3.87-4.00(1H, m), 4.09(1H, dd), 4.43-4.67(2H, m),6.65(1H, d), 6.70-6.90(3H, m), 7.10-7.40(7H, m), 7.40-7.73(3H, m),7.83(1H, brs), 8.98(1H, brs)

IR(KBr)cm⁻¹:3337, 1651

MS(FAB)m/z: 648(M+K)⁺

Example 42

Preparation of3-[3-(3-methylsulfonylaminocarbonylphenyl)ureido]-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-1-ylacetic acid

Trifluoroacetic acid (0.32 ml) was added to a solution of1-(1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea(400 mg) obtained from example 16 in anhydrous 1,2-dichloroethane (10ml), the mixture was refluxed for 5 hours. Methylene chloride (30 ml)and saturated aqueous sodium bicarbonate were added to the reactionmixture and separated into organic layer and aqueous layer, the aqueouslayer was adjusted to pH 2 with 1N hydrochloric acid, and extracted withethyl acetate. The extraction was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. Isopropyl ether was added to the residue fortrituration and filtrated, to thereby obtain 226 mg of the titlecompound as a yellow solid (Yield: 64.0%).

¹H-NMR(DMSO-d₆) δ: 3.34(3H, s), 3.55-3.69(1H, m), 3.95-4.08(1H, m),4.47-4.65(3H, m), 6.73-6.88(4H, m), 7.10-7.62(9H, m), 7.91(1H, br s),9.13(1H, brs), 12.04(1H, br), 12.83(1H, br)

IR(KBr)cm⁻¹:3364, 1654, 1593, 1559

MS(FAB)m/z: 552(MH)⁺

Example 43

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

m-Tolyl isocyanate (34 mg) was added to a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(90 mg) obtained from Step 2 of Example 18 in tetrahydrofuran (10 ml),the mixture was stirred for 10 minutes at room temperature. The reactionmixture was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=3:1), to thereby obtain 100 mg of the title compound (Yield:83%).

Melting point: 196.5-197.5° C.

¹H-NMR(CDCl₃) δ: 2.19(3H, s), 2.45(3H, s), 3.68(1H, dd), 4.23(1H, dd),4.92(1H, d), 4.93-5.02(1H, m), 5.31(1H, d), 6.50(1H, d), 6.721-7.66(18H,m)

MS(FAB)m/z: 519(MH⁺)

Example 44

Preparation of1-[1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Methyl iodide (1.4 ml) and sodium bicarbonate (630 mg) were added to asolution of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(832 mg) in methanol (20 ml), the mixture was refluxed for 2 days. Thereaction mixture was concentrated under reduced pressure, Water (30 ml)was added to the residue and extracted with methylene chloride. Theorganic layer was washed with saturated brine, dried over anhydroussodiun sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform:methanol=50:1), to thereby obtain 585 mg of the titlecompound (Yield: 66.9%) as brown amorphous.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 2.81(3H, s), 3.29-3.42(1H, m), 3.59(1H,dd), 4.37-4.50(1H, m), 5.46-5.60(1H, m), 6.90-7.22(4H, m), 7.52(1H, brs)

Step 2

Preparation of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Bromo-N-methyl-N-phenylacetamide (602 mg), 1N aqueous sodium hydroxide(10 ml) and tetra n-butylammonium bromide (58 mg) were added to asolution of2-oxo-3-tert-butoxycarbonylamino-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(514 g) in toluene (15 ml), the mixture was stirred overnight at roomtemperature. Water (100 ml) was added to the reaction mixture andextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodiun sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=1:1), tothereby obtain 553 mg of the title compound (71.6%) as a white solid.

¹H-NMR(CDCl₃) δ: 1.38(9H, s), 2.69(3H, s), 3.22(1H, dd), 3.35(3H, s),3.49(1H, t), 3.62(1H, d), 4.36-4.49(1H, m), 4.73(1H, d), 5.55-5.66(1H,m), 6.93-7.48(9H, m)

Step 3

Preparation of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

4N-HCl dioxane (5.0 ml) was added to a suspension of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(550 mg) in ethanol (25 ml), the mixture was stirred at 50° C. for onehour. The reaction mixture was concentrated under reduced pressure,methylene chloride (50 ml) was added to the residue. The mixture waswashed with saturated aqueous sodium bicarbonate, dried over anhydroussodiun sulfate, and the solvent was evaporated under reduced pressure,to thereby obtain 414 mg of the title compound (Yield: 97.9%) asamorphous.

¹H-NMR(CDCl₃) δ: 1.62(2H, brs), 2.69(3H, s), 3.07-3.30(2H, m), 3.36(3H,s), 3.46-3.69(2H, m), 4.83(1H, d), 6.96-7.48(9H, m)

Step 4

Preparation of1-[1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆, 100° C.) δ: 2.69(3H, s), 3.20(1H, dd), 3.24(3H, s),3.32(1H, dd), 3.85(1H, d), 4.40(1H, ddd), 4.58(1H, d), 6.36(1H, d),7.03-7.52(14H, m), 7.80(1H, t), 8.68(1H, brs)

IR(KBr)cm⁻¹:3368, 1654, 1559, 1541, 1499

MS(FAB)m/z: 579(MH)⁺

Example 45

Preparation of1-[1-(2,2-diethoxyethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that2-oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.97(9H, s), 3.94(1H, dd), 4.38(1H, t), 4.45-4.58(1H,m), 5.07(2H, s), 5.70(1H, d), 7.14(1H, d), 7.24-7.45(8H, m), 7.92(1H, s)

Step 2

Preparation of1-(2,2-diethoxyethyl)-2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that bromoacetaldehyde diethylacetal was used instead of2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.96(9H, s), 1.24(3H, t), 1.25(3H, t), 3.24(1H, dd),3.50-3.90(5H, m), 4.23-4.32(2H, m), 4.45-4.49(1H, m), 4.96(1H, dd),5.06(2H, s), 5.68(1H, d), 7.17-7.47(8H, m), 7.91(1H, dd)

Step 3

Preparation of1-[1-(2,2-diethoxyethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 38 was repeated except that1-(2,2-diethoxyethyl)-2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-phenyl-2-oxo-3-benzyloxycarbonylamino-5-isobutyryl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 167-169° C.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.22(3H, t), 1.25(3H, t), 2.30(3H, s),3.22(1H, dd), 3.48-3.96(5H, m), 4. 32(1H, t), 442(1H, dd), 4.64-4.76(1H,m), 4.94(1H, dd), 6.16(1H, d), 6.83(1H, d), 7.06-7.53(7H, m), 7.94(1H,dd)

MS(FAB) m/z: 465(M-OC₂H⁵)⁺

Example 46

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 1 of Example 33 was used instead of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 229-233° C.

¹H-NMR(DMSO-d₆) δ: 1.17(9H, s), 2.97(3H, s), 3.50-3.66(1H, m),3.90-4.11(1H, m), 4.50-4.65(1H, m), 4.76(1H, d), 5.12(1H, d), 6.66(1H,d), 6.73-6.88(3H, m), 7.09-7.34(7H, m), 7.42-7.59(2H, m), 7.81(1H, brs),8.97(1H, brs), 12.07(1H, br)

MS(FAB)m/z: 592(MH)⁺

Example 47

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-methylsulfonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-methylsulfonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 3 was repeated except that methanesulfonyl chloridewas used instead of 1-adamantylcarbonyl chloride, to thereby obtain thetitle compound.

¹H-NMR(DMSO-d₆) δ: 1.34(9H, s), 3.02(3H, s), 3.77-3.87(1H, m),4.07-4.28(2H, m), 7.17(1H, d), 7.21-7.31(2H, m), 7.38-7.48(2H, m),10.00(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methylsulfonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 3 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-methylsulfonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 2.55(3H, s), 3.03(3H, s), 4.00-4.23(2H,m), 4.53-4.69(2H, m), 5.48(1H, d), 5.59(1H, d), 7.22-7.55(7H, m) ),7.75(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-methylsulfonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 3 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methylsulfonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 209-211° C. (decomposition)

¹H-NMR(CDCl₃) δ: 2.26(3H, s), 2.52(3H, s), 3.06(3H, s), 4.10-4.25(2H,m), 4.62(1H, d), 4.80-4.93(1H, m), 5.49(1H, d), 6.08(1H, d),6.73-7.74(13H, m)

MS(FAB)m/z: 521(MH)⁺

Example 48

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(pyridin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(pyridin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 3 was repeated except that 2-pyridylcarbonyl chloridewas used instead of 1-adamantylcarbonyl chloride, to thereby obtain thetitle compound.

¹H-NMR(DMSO-d₆) δ: 1.37(9H, s), 3.75(1H, dd), 4.22-4.37(1H, m), 4.59(1H,t), 6.80-6.88(2H, m), 7.08(1H, d), 7.13-7.28 (2H, m), 7.30-7.43(2H, m),7.71(1H, d), 10.12(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(pyridin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 3 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(pyridin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.59(3H, s), 4.10-4.23(1H, m), 4.47(1H,t), 4.61(1H, d), 4.69-4.85(1H, m), 5.60-5.74(2H, m), 6.76(1H, d),6.90-7.00(1H, m), 7.08-7.48(6H, m), 7.58-7.72(2H, m), 7.82(1H, d),8.14(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(pyridin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 3 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(pyridin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 238-240° C. (decomposition)

¹H-NMR(CDCl₃) δ: 2.26(3H, s), 2.55(3H, s), 4.20(1H, dd), 4.56(1H, t),4.67(1H, d), 5.65(1H, d), 6.15(1H, d), 6.73-7.87(16H, m), 8.15(1H, d)

MS(FAB)m/z: 548(MH)⁺

Example 49

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-methoxycarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-methoxycarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 3 was repeated except that methyl chloroformate wasused instead of 1-adamantylcarbonyl chloride, to thereby obtain thetitle compound.

¹H-NMR(DMSO-d₆) δ: 1.34(9H, s), 3.45-3.75(4H, m), 4.05-4.42(2H, m),7.12(1H, d), 7.16-7.28(2H, m), 7.30-7.40(2H, m), 9.89(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methoxycarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 3 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-methoxycarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.33(9H, s), 2.35(3H, s), 3.50-3.76(4H, m),4.17-4.53(2H, m), 5.04-5.25(2H, m), 7.26-7.52(8H, m), 7.80-7.90(1H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-methoxycarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 3 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-methoxycarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(adamantan-1-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆, 100° C.) δ: 2.21(3H, s), 2.38(3H, s), 3.61(3H, s),3.81(1H, dd), 4.12(1H, dd), 4.54(1H, ddd), 5.04(1H, d), 5.14(1H, d),6.50(1H, d), 6.71(1H, m), 7.00-7.18(3H, m), 7.24-7.48(7H, m),7.74-7.81(1H, m), 8.48(1H, brs)

MS(FAB)m/z: 501(MH)⁺

Example 50

Preparation of1-(1-tert-butoxycarbonylmethyl)-2-oxo-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

4N HCl-dioxane (10 ml) was added to a solution of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) obtained from Step 1 of Example 14 in ethanol (30 m1), themixture was stirred at 50° C. for one hour. The reaction mixture wasconcentrated under reduced pressure, saturated aqueous sodiumbicarbonate was added to the residue and extracted with chloroform.After the organic layer was dried over anhydrous sodiun sulfate, thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (10 ml), a solution of sodium carbonate (274 mg) inwater (10 ml) and a solution of benzyl chloroformate (440 mg) intetrahydrofuran (10 ml) were added, and the mixture was stirred at roomtemperature for one hour. This solution was extracted with ethylacetate, washed with saturated brine, dried over anhydrous sodiunsulfate, and the solvent was evaporated under reduced pressure.Isopropyl ether was added to the obtained solid for trituration andfiltrated, to thereby obtain 890 mg of the title compound (Yield:82.0%).

¹H-NMR(CDCl₃) δ: 0.75-2.05(11H, m), 3.80-3.89(1H, m), 4.51-4.67(2H, m),5.06(2H, s), 5.69(1H, br), 7.14-7.47(9H, m), 7.75(1H, s)

Step 2

Preparation of1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under ice-cooling,2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(800 mg) was added to a suspension of 60% sodium hydride (152 mg) intetrahydrofuran (50 ml), the mixture was stirred at room temperature forone hour. Subsequently, tert-butyl bromoacetate (390 mg) was added andstirred at room temperature for one hour. The reaction mixture wasconcentrated under reduced pressure, Water was added to the residue andextracted with methylene chloride. The organic layer was washed withsaturated brine, dried over anhydrous sodiun sulfate, and the mixturewas purified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 640 mg of the title compound (Yield:63%).

¹H-NMR(CDCl₃) δ: 0.98(9H, s), 1.50(9H, s), 3.84(1H, d), 3.91(1H, dd),4.27(1H, t), 4.46-4.56(1H, m), 4.78(1H, d), 5.05(2H, s), 5.74(1H, d),7.21-7.48(9H, m)

Step 3

Preparation of1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 16 was repeated except that1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.90-2.20(20H, m), 2.29(3H, s), 3.85(1H, dd), 4.03(1H,d), 4.51(1H, t), 4.71-4.92(2H, m), 6.19(1H, d), 6.82(1H, brs),7.06-7.55(7H, m), 7.61(1H, s)

Step 4

Preparation of1-(1-tert-butoxycarbonylmethyl-2-oxo-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 4 of Example 1 was repeated except that1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 143-145° C.

¹H-NMR(CDCl₃) δ: 0.90-2.20(20H, m), 2.29(3H, s), 3.85(1H, dd), 4.03(1H,d), 4.51(1H, t), 4.71-4.92(2H, m), 6.19(1H, d), 6.82(1H, brs),7.06-7.55(7H, m), 7.61(1H, s)

MS(FAB)m/z: 535(MH⁺)

Example 51

Preparation of1-(1-tert-butylcarbonylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 10 was used instead of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 216-220° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.93(9H, s), 1.20(3H, s), 2.87(3H, s), 3.68(1H, dd),4.19(1H, t), 4.41(1H, d), 4.37-4.51(1H, m), 5.17(1H, d), 6.50-6.62(1H,m), 7.12-7.26(2H, m), 7.36-7.58(6H, m), 7.77(1H, brs), 8.85(1H, brs)

MS(FAB) m/z: 600(MH)⁺

Example 52

Preparation of1-[1-(N,N-dimethyl)carbamoylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of1-(N,N-dimethylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-bromo-N-methyl-N-phenylacetamide was used instead of2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.01(9H, s), 1.39(9H, s), 3.05(3H, s), 3.10(3H, s),3.83(1H, d), 3.90-4.03(1H, m), 4.21(1H, t), 4.41-4.56(1H, m), 5.14(1H,d), 5.55(1H, d), 7.17-7.51(4H, m)

Step 2

Preparation of1-[1-(N,N-dimethylcarbamoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(N,N-dimethylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, the titlecompound was obtained.

Melting point: 252-254° C.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 2.23(3H, s), 3.00(3H, s), 3.08(3H, s),3.90(1H, d), 3.99(1H, dd), 4.35(1H, t), 4.76(1H, ddd), 5.16(1H, d),6.14(1H, d), 6.77(1H, d), 6.97-7.50(8H, m)

MS(FAB)m/z: 480(MH)⁺

Example 53

Preparation of1-[1-(pyrrolidin-1-yl)carbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of1-(pyrrolidin-1-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that 1-bromo acetylpyrrolidinewas used instead of 2-bromo-2′-methylacetophenone, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 1.01(9H, s), 1.39(9H, s), 1.82-2.12(4H, m),3.36-3.72(4H, m), 3.77(1H, d), 3.89-4.00(1H, m), 4.21(1H, t),4.40-4.54(1H, m), 5.01(1H, d), 5.47-5.58(1H, m), 7.16-7.45(3H, m),7.59(1H, d)

Step 2

Preparation of1-[1-(pyrrolidin-1-yl)carbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-(pyrrolidin-1-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, the titlecompound was obtained.

Melting point: 246-248° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.80-2.08(4H, m), 2.24(3H, s),3.36-3.70(4H, m), 3.85(1H, d), 3.98(1H, dd), 4.35(1H, t), 4.76(1H, ddd),5.03(1H, d), 6.08(1H, d), 6.78(111, m), 6.98-7.61(8H, m)

MS(FAB)m/z: 506(MH)⁺

Example 54

Preparation of1-[1-[N-(2-dimethylaminoethyl)-N-methylcarbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of1-benzyloxycarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that benzyl bromoacetate wasused instead of 2-bromo-2′-methylacetophenone, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 0.98(9H, s), 1.40(9H, s), 3.91(1H, dd), 4.02(1H, d),4.24(1H, t), 4.41-4.56(1H, m), 4.91(1H, d), 5.26(2H, s), 5.48(1H, d),7.20-7.44(9H, m)

Step 2

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-1-yl-aceticacid

10% Palladium carbon (300 mg) was added to a suspension of1-benzyloxycarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(3.0 g) in methanol (100 ml), the mixture was stirred for 30 minutesunder hydrogen atmosphere. The reaction mixture was filtrated and thefiltrate was concentrated under reduced pressure. Isopropyl ether wasadded to the residue for trituration and filtrated, to thereby obtain2.46 g of the title compound (Yield: 99.6%) as pale yellow powder.

¹H-NMR(DMSO-d₆) δ: 0.92(9H, s), 1.34(9H, s), 3.47(1H, dd), 4.00-4.24(2H,m), 4.38(1H, t), 4.52(1H, d), 7.28(1H, d), 7.34-7.58(4H, m),12.0-13.0(1, br)

Step 3

Preparation of1-[N-(2-dimethylaminoethyl)-N-methylcarbamoylmethyl]-2-6xo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine4-Dimethylaminopyridine (426 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (728 mg) andN,N,N′-trimethylethylenediamine (419 mg) was added to a suspension of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-1-yl-aceticacid (1.01 g) in anhydrous methylene chloride (50 ml), the mixture wasstirred for one hour at room temperature. The reaction mixture wasconcentrated under reduced pressure, ethyl acetate (100 ml) was added tothe residue, washed with water and dried over anhydrous sodiun sulfate.The solvent was evaporated under reduced pressure, purified by silicagel column chromatography (chloroform:methanol=10: l), Ether was addedto the residue for trituration, to thereby obtain 383 mg of the titlecompound as pale yellow powder.

Step 4

Preparation of1-[1-[N-(2-dimethylaminoethyl)-N-methylcarbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that1-[N-(2-dimethylaminoethyl)-N-methylcarbamoylmethyl]-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 216-218° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.01 and 1.02(9H, each s), 2.23 and 2.25(9H, each s),2.33-2.58(2H, m), 2.99 and 3.09(3H, each s), 3.21-3.54(2H, m),3.84-4.16(2H, m), 4.26-4.40(1H, m), 4.69-4.82(1H, m), 5.14 and 5.18(1H,each d), 6.12(1H, d), 6.72-7.49(9H, m)

MS(FAB)m/z: 537(MH)⁺

Example 55

Preparation of1-[1-(4-methylpiperazin-1-yl)carbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 54 was repeated except that 1-methylpiperazine wasused instead of N,N,N′-trimethylethylenediamine, subsequently, in asimilar manner to Step 3 and 4 of Example 1, to thereby obtain the titlecompound.

Melting point: 233-234° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 2.19-2.52(4H, m), 2.24(3H, s), 2.30(3H,s), 3.36-3.80(4H, m), 3.88(1H, d), 3.99(1H, dd), 4.36(1H, t), 4.79(1H,dt), 5.19(1H, d), 6.12(1H, d), 6.73-7.46(9H, m)

MS(FAB)m/z: 535(MH)⁺

Example 56

Preparation of sodium(+)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoate

Step 1

Preparation of(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

(+)-Dibenzoyltartaric acid (5.19 g) was added to a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(5.48 g) obtained from Step 3 of Example 1 in ethyl acetate (150 ml)under agitation, crystals so precipitated were collected by filtration.Saturated aqueous sodium bicarbonate was added this crystals, extractedwith chloroform, dried over anhydrous sodiun sulfate, and the solventwas evaporated under reduced pressure, to thereby obtain crude(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.This crude compound was dissolved in ethyl acetate (150 ml) again,(+)-dibenzoyltartaric acid (2.60 g) was added under agitation andcrystals so precipitated were collected by filtration. Saturated aqueoussodium bicarbonate was added this crystals, extracted with chloroform,dried over anhydrous sodiun sulfate, and the solvent was evaporatedunder reduced pressure, to thereby obtain 2.55 g of the title compound.

[α] D²⁵ (C=0.60, CHCl₃): +84.3°

Step 2

Preparation of(−)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Saturated aqueous sodium bicarbonate was added the filtrate obtainedfrom Step 1, extracted with chloroform, dried over anhydrous sodiunsulfate, the solvent was evaporated, (−)-dibenzoyltartaric acid wasadded to the obtained residue, and in a similar manner to Step 1, tothereby obtain 2.44 g of the title compound.

[α] D²⁵ (C=1.00, CHCl₃): −84.0°

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)ureaDiphenylphosphoryl azide (1.183 g) and triethylamine (455 mg) were addedto a solution of isophthalic acid monobenzyl ester (1.073 g) in dioxane(50 ml), the mixture was stirred at 80° C. until bubbling was finished.The reaction mixture was allowed to cool at room temperature,(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.023 g) was added to this reaction mixture and then stirred for 30minutes at room temperature. The resultant mixture was concentratedunder reduced pressure, methylene chloride was added to the residue,successively washed with saturated aqueous sodium bicarbonate andsaturated brine, dried over anhydrous sodiun sulfate. The mixture waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 1.61 g of the title compound (Yield:93.7%).

¹H-NMR(CDCl₃) δ: 1.0(9H, s), 2.47(3H, s), 4.00(1H, dd), 4.38(1H, t),4.39(1H, d), 4.77-4.89(1H, m), 5.32(2H, s), 5.50(1H, d), 6.32(1H, d),7.12-7.46(13H, m), 7.57-7.67(4H, m), 7.92(1H, t)

Step 4

Preparation of sodium(+)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoate

10% Palladium carbon (200 mg) was added to a solution of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea(1.4 g) obtained from Step 3 in ethanol (50 ml), stirred for 8 hours atroom temperature under hydrogen atmosphere. The reaction mixture wasfiltrated and the filtrate was concentrated under reduced pressure, tothereby obtain 1.04 g of(+)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid (Yield: 86%).

[α] D²⁰ (C=0.45, CHCl₃): +15.8°

¹H-NMR(CDCl₃) δ: 1.09(9H, s), 2.55(3H, s), 4.12(1H, dd), 4.45(1H, t),4.59(1H, d), 4.77-4.89(1H, m), 5.51(1H, d), 7.17-7.75(13H, m),8.18-8.38(2H, m)

Furthermore, the compound so obtained was converted into its sodium saltin a manner known per se in the art, to obtain the title compound.

Melting point: 210-212° C.

Example 57

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(4-hydroxy-2-oxo-5H-thiolen-3-yl)carbonylphenyl]urea

2-Chloro-1,3-dimethylimidazoliniumchloride (355 mg) was added to asolution of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid (780 mg) in methylene chloride (20 ml), stirred at room temperaturefor 15 minutes, thiotetronic acid (198 mg) and triethyl amine (425 mg)were added, and the mixture was stirred for 30 minutes at roomtemperature. 1N hydrochloric acid (10 ml) was added to the reactionmixture and separated into organic layer and aqueous layer, the aqueouslayer was extracted with methylene chloride. The organic layer wascombined, and washed with the water, dried over anhydrous sodiunsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform:methanol=20:1), and recrystallized from the mixed solvent ofisopropyl ether and ethanol, to thereby obtain 660 mg of the titlecompound (Yield: 72.0%) as a light peach color solid.

Melting point: 206-208° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.07(9H, s), 2.44(3H, s), 3.91(1H, dd), 4.18(2H, d),4.44(1H, t), 4.48(1H, d), 4.86-5.03(1H, m), 5.68(1H, d), 6.54(1H, t),6.73(1H, d), 7.13-7.58(11H, m), 7.73(1H, d), 8.02(1H, t)

MS(FAB)m/z: 655(MH)⁺

Example 58

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(4-hydroxy-2-oxo-5H-oxolen-3-yl)carbonylphenyl]urea

Example 57 was repeated except that tetronic acid was used instead ofthiotetronic acid, to thereby obtain the title compound.

Melting point: 208-209° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.96(9H, s), 2.45(3H, s), 3.72(1H, dd), 4.29(1H, t),4.45-4.60(1H, m), 4.90(2H, d), 5.16(2H, d), 5.47(2H, d), 6.13(1H, t),6.77(1H, d), 7.30-7.67(10H, m), 7.97(1H, d), 8.21(1H, brs), 9.21(1H,brs)

MS(FAB)m/z: 639(MH)⁺

Example 59

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(N,N-dimethylamino)phenyl]urea

1,1′-Carbonyldiimidazole (244 mg) was added to a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(393 mg) in anhydrous tetrahydrofuran (5 ml), stirred for 30 minutes atroom temperature,N,N-dimethyl-m-phenylenediamine dihydrochloride (335mg) and triethylamine (0.67 ml) was added, and the mixture was refluxedovernight. The reaction mixture was concentrated under reduced pressure,appeared insoluble material was removed and purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=1:1). Etanol was added tothe residue for crystallization and filtrated, to thereby obtain 224 mgof the title compound (Yield: 40.3%) as white solid.

Melting point: 219-221° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 2.53(3H, s), 2.91(6H, s), 4.04(1H, dd),4.31(1H, t), 4.44(1H, d), 4.76-4.89(1H, m), 5.49(1H, d), 6.03(1H, d),6.40-6.52(2H, m), 6.66(1H, brs), 6.76-6.83(1H, m), 7.11(1H, t),7.20-7.47(7H, m), 7.69(1H, d)

MS(FAB)m/z: 556(MH)⁺

Example 60

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(piperidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-[(N-benzyloxycarbonyl)piperidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Isobutyl chloroformate (983 mg) and N-methylmorpholine (728 mg) wereadded to a solution of (N-benzyloxycarbonyl)pipecolinic acid (1.90 g) inanhydrous 1,2-dichloroethane (50 ml) at 0° C., stirred at roomtemperature for 15 minutes.2-Oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) was added thereto, the mixture was refluxed for 5 hours. Thereaction mixture was allowed to cool, methylene chloride was added andsuccessively washed with water and saturated brine. The extract wasdried over anhydrous sodiun sulfate, the solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 802 mg ofthe title compound (Yield: 42.6%) as colorless amorphous.

¹H-NMR(CDCl₃) δ: 1.10-2.10(15H, m), 3.00-4.20(3H, m), 4.35-4.75(3H, m),4.82-4.95(1H, m), 5.04-5.18(1H, m), 5.33-5.53(1H, m), 6.60-7.80(9H, m)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-[(N-benzyloxycarbonyl)piperidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-[(N-benzyloxycarbonyl)piperidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.20-2.20(15H, m), 2.50-2.60(3H, m), 3.10-5.60(11H, m),6.60-7.90(13H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(piperidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

4N HCl-dioxane (10 ml) was added to a solution of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-[(N-benzyloxycarbonyl)piperidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(845 mg) in ethanol (30 ml), then stirred at 50 ° C. for 15 minutes. Thereaction mixture was concentrated under reduced pressure, saturatedaqueous sodium bicarbonate was added and extracted with chloroform.After the organic layer was dried over anhydrous sodium sulfate, thesolvent was evaporated under reduced pressure, the residue was dissolvedin tetrahydrofuran (20 ml), m-tolylisocyanate (0.18 ml) was added to thesolution, and the mixture was stirred at room temperature for 15minutes. This resultant mixture was concentrated under reduced pressure,purified by silica gel column chromatography (chloroform:methanol=20:1),and isopropyl ether was added to the residue for trituration andcollected by filtration. 25% hydrobromic acid-acetic acid solution (10ml) was added to the collection, then stirred at room temperature for 30minutes, ether was added to reaction mixture. Solid so precipitated wascollected by filtration, saturated aqueous sodium bicarbonate was addedand extracted with chloroform. After the organic layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, purified by silica gel column chromatography (chloroform:methanol=20:1), separated into first eluent that was compound A andsecond eluent that was compound B.

Ethanol was added to the (A) and solidified, to thereby obtain 22 mg ofthe title compound(A′). The mixed solvent of isopropyl ether and ethanolwas added to the (B) and solidified, to thereby obtain 42 mg of thetitle compound(B′).

Physicochemical data of (A′)

Melting point: 207-210° C. (decomposition)

¹H-NMR(DMSO-d₆, 25° C.) δ: 1.00-1.80(6H, m), 2.22(3H, s), 2.41(3H, s),2.70-3.40(3H, m), 3.53-3.65(1H, m), 4.38-4.60(2H, m), 4.96(1H, d),5.42(1H, d), 6.66-6.80(2H, m), 7.03-7.20(2H, m), 7.30-7.62(8H, m),7.93(1H, d), 8.71(1H, s), 8.86(1H, s)

MS(FAB)m/z: 554(MH)⁺

Physicochemical data of (B′)

Melting point: 202-204° C. (decomposition)

¹H-NMR(DMSO-d₆, 25° C.) δ: 1.00-1.73(6H, m), 2.90-3.40(3H, m), 2.22(3H,s), 2.37(3H, s), 3.66(1H, dd), 4.32(1H, t), 4.48-4.64(1H, m), 5.23(1H,d), 5.34(1H, d), 6.64-6.77(2H, m), 7.03-7.19(3H, m), 7.29-7.68(8H, m),7.95(1H, d), 8.72(1H, brs)

MS(FAB)m/z: 554(MH)⁺

Example 61

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(tetrazol-5-yl)phenyl]urea

Triethylamine (0.44 ml) was added to a suspension of5-(3-aminophenyl)tetrazole hydrochloride (prepared according toInternational Publication WO93/17011) (316 mg) in anhydroustetrahydrofuran (10 ml). After cooled at 0° C., triphosgene (157 mg) wasadded, and the mixture was adjusted to pH 8 with triethylamine (0.22ml). After returned at room temperature, stirred for 30 minutes,1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(472 mg) obtained from Step 3 of Example 1 in anhydrous tetrahydrofuran(10 ml) was added to the reaction mixture, and then stirred at roomtemperature for one hour. Ethyl acetate (20 ml) was added to theresultant mixture, 10% acetic acid (20 ml) was added thereto andseparated into organic layer and aqueous layer. After the organic layerwas dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=5:1) and the mixed solvent ofisopropyl ether and ethanol was added to the residue for trituration,collected by filtration, to thereby obtain 443 mg of the title compound(Yield: 63.6%) as white powder.

Melting point: 187-203° C.

¹H-NMR(DMSO-d₆) δ: 0.96(9H, s), 2.45(3H, s), 3.73(1H, dd), 4.30(1H, t),4.48-4.62(1H, m), 4.92(1H, d), 5.47(1H, d), 6.78(1H, d), 7.32-7.62(11H,m), 7.98(1H, d), 8.10(1H, brs), 9.09(1H, brs)

MS(FAB)m/z: 581(MH)⁺

Example 62

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(5-oxo-4H-1,2,4-oxadiazolin-3-yl)phenyl]urea

Example 61 was repeated except that3-(3-aminophenyl)-5-oxo-4H-1,2,4-oxadiazoline hydrochloride (preparedaccording to Japanese Patent publication (Kohyo) Hei.7-504908) was usedinstead of 5-(3-aminophenyl)tetrazole hydrochloride, to thereby obtainthe title compound.

Melting point: 179-182° C.

¹H-NMR(CDCl₃) δ: 1.10(9H, s), 2.03(3H, s), 3.86(1H, dd), 4.52(1H, t),4.56(1H, d), 5.04-5.20(1H, m), 5.75(1H, d), 6.62(1H, brs), 6.87(1H, d),7.0-7.54(11H, m), 7.78(1H, dd), 10.75(1H, br)

MS(FAB)m/z: 597(MH)⁺

Example 63

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(N-hydroxycarbamoyl)phenyl]urea

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(N-benzyloxycarbamoyl)phenyl]urea

Triethylamine (0.28 ml) was added to a suspension ofo-benzylhydroxylamine hydrochloride (319 mg) in anhydrous methylenechloride (10 ml) at 0° C.,3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid (557 mg) obtained from Example 37,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (383 mg) andtriethylamine (0.56 ml) were added, the mixture was stirred for at roomtemperature 2 hours. Methylene chloride (50 ml) was added to thereaction mixture, successively washed with 1N hydrochloric acid,saturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, the residue was purified bysilica gel column chromatography (chloroform:methanol=20:1), to therebyobtain 420 mg of the title compound (Yield: 63.5%) as colorless oil.

¹H-NMR(CDCl₃) δ: 1.09(9H, s), 2.26(3H, s), 3.86(1H, dd), 4.46(1H, t),4.55(1H, d), 4.95(2H, ABq), 5.02-5.14(1H, m), 5.70(1H, d), 6.71(1H, d),6.93(1H, t), 7.02(1H, brs), 7.11-7.47(15H, m), 7.76(1H, d), 10.10(1H,brs)

Step 2

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(N-hydroxycarbamoyl)phenyl]urea

Step 5 of Example 31 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(N-benzyloxycarbamoyl)phenyl]ureawas used instead of1-[1-[N-(1-methylpiperidin-4-yl)]carbamoylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)ureahydrochloride, to thereby obtain the title compound.

Melting point: 192-196° C.

¹H-NMR(DMSO-d₆) δ: 0.95(9H, s), 2.45(3H, s), 3.71(1H, dd), 4.27(1H, t),4.44-4.60(1H, m), 4.90(1H, d), 5.46(1H, d), 6.71(1H;d), 7.20-7.61(10H,m), 7.70(1H, brs), 7.97(1H, d), 8.95(2H, brs), 11.09(1H, brs)

MS(FAB)m/z: 572(MH)⁺

Example 64

Preparation ofN-[3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoyl]glycine

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(N-ethoxycarbonylmethyl)carbamoylphenyl]urea

Step 1 of Example 63 was repeated except that glycine ethylester wasused instead of o-benzylhydroxylamine hydrochloride, to thereby obtainthe title compound.

¹H-NMR(CDCl₃) δ: 1.08(9H, s), 1.27(3H, t), 2.40(3H, s), 3.88(1H, d),4.03(1H, dd), 4.14-4.28(3H, m), 4.42(1H, t), 4.54(1H, d), 4.90-5.05(1H,m), 5.64(1H, d), 6.56(1H, d), 7.07(1H, t), 7.20-7.52(12H, m), 7.75(1H,d)

Step 2

Preparation ofN-[3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoyl]glycine

Lithium hydroxide (151 mg) in water (1 0 ml) was added to a solution of1-[L-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-[3-(N-ethoxycarbonylmethyl)carbamoylphenyl]urea(465 mg) in methanol (30 ml), the mixture was stirred at roomtemperature for one hour. The reaction mixture was concentrated underreduced pressure, adjusted to pH 2 with 1N hydrochloric acid andextracted with methylene chloride. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and the solventwas evaporated under reduced pressure. The mixed solvent of isopropylether and ethanol was added to the obtained compound and solidified andcollected by filtration, to thereby obtain 320 mg of the title compound(Yield: 72.4%).

Melting point: 180-187° C.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 2.40(3H, s), 3.50-5.00(1H, br),3.77-3.89(1H, m), 3.95-4.16(2H, m), 4.47(1H, t), 4.61(1H, d),4.69-4.95(1H, m), 5.49(1H, d), 6.75(1H, d), 7.05(1H, t), 7.17-7.52(11H,m), 7.58-7.82(2H, m)

MS(FAB)m/z: 614(MH)⁺

Example 65

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonylphenyl)urea

Step 3 of Example 10 was repeated except that methyl 3-amino benzoatewas used instead of ethyl 3-amino benzoate and that1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 3 of Example 1 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 201-207° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 2.49(3H, s), 3.85(3H, s), 4.00(1H, dd),4.39(1H, t), 4.42(1H, d), 4.87(1H, d t), 5.54(1H, d), 6.30(1H, d),7.16-7.69(12H, m), 7.93-7.99(1H, m)

MS(FAB)m/z: 571(MH)⁺

Example 66

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(piperidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(1-benzyloxycarbonylpiperidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(1-benzyloxycarbonylpiperidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 60 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,subsequently, in a similar manner to Step 3 of Example 56, to therebyobtain the compound. The compound was purified by silica gel columnchromatography (methylene chloride:ethyl acetate=20:1), was separatedinto 1.26 g of first eluent that was yellow oily title compound A and0.93 of second eluent that was yellow oily title compound B.

Physicochemical data of (A)

¹H-NMR(DMSO-d₆, 100° C.) δ: 1.20-2.10(6H, m), 2.45(3H, s), 3.00-3.20(1H,m), 3.70-3.88(2H, m), 4.34(1H, t), 4.47-4.65(2H, m), 4.67-4.83(2H, m),4.90(1H, d), 5.32(2H, s), 6.54(1H, d), 7.15-7.62(20H, m), 7.71(1H, d),8.00(1H, t), 8.91(1H, brs)

Physicochemical data of (B)

¹H-NMR(CDCl₃) δ: 1.20-1.80(6H, m), 2.48(3H, s), 3.40-3.68(1H, m),3.80-4.20(2H, m), 4.40-4.60(2H, m), 4.70-5.25(4H, m), 5.30(2H, s),5.35-5.60(1H, m), 6.22(1H, d), 6.78(1H, br), 7.05-7.83(21H, m), 7.94(1H,d)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(piperidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride Compound(B) (860 mg) obtained from Step 1 wasdissolved in methanol (20 ml), palladium hydroxide (86 mg) and 1Nhydrochloric acid (1.2 m) were added, and then stirred at roomtemperature for 3 hours under hydrogen atmosphere. After the reactionmixture was filtrated and the filtrate was concentrated under reducedpressure, toluene was added and azeotropic distilled. The mixed solventof isopropyl ether and ethanol was added to the obtained compound andsolidified and collected by filtration, to thereby obtain 600 mg of thetitle compound(B1) (Yield: 91.3%).

Melting point: 221-226° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.00-1.85(6H, m), 2.70-4.00(4H, m), 4.36(1H, t),4.54-4.68(1H, m), 5.11(1H, d), 5.39(1H, d), 6.93(1H, d), 7.28-8.05(12H,m), 8.74(1H, br), 9.31(1H, brs), 9.48(1H, br), 12.80(1H, br)

MS(FAB)m/z: 584(MH)⁺

Furthermore, same procedure was carried out for compound(A), to therebytitle compound(A1).

Melting point: 222-226° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.00-2.30(6H, m), 2.37(3H, s), 2.80-3.60(3H, m),3.68-3.85(1H, m), 4.48-4.68(2H, m), 5.31(1H, d), 5.58(1H, d), 7.01(1H,d), 7.28-7.75(10H, m), 7.85-8.04(2H, m), 8.70-9.30(3H, m), 12.80(1H, br)

MS(FAB)m/z: 584(MH)⁺

Example 67

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(pyrrolidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-[(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 60 was repeated except that(N-benzyloxycarbonyl)proline was used instead of(N-benzyloxycarbonyl)pipecholinic acid. The resultant product waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1), to thereby obtain 1.68 g of first eluent that wascolorless oily title compound(A) and 1.34 g of second eluent that wascolorless solid title compound (B).

Physicochemical data of (A)

¹H-NMR(DMSO-d₆, 100° C.) δ: 1.37(9H, m), 1.65-2.15(4H, m), 3.30-3.47(2H,m), 3.50-4.04(2H, m), 4.15-4.30(11H, m), 4.46-4.70(11H, m),4.92-5.12(2H, m)), 6.68(11H, d), 7.18-7.48(9H, m), 9.65(1H, brs)

Physiochemical data of (B)

¹H-NMR(DMSO-d₆, 100° C.) δ: 1.34(9H, s), 1.45-1.90(4H, m), 3.28-3.60(3H,m), 4.08-4.26(2H, m), 4.50-4.68(1H, m), 5.06(2H, s), 6.60-6.72(1H, m),6.80-7.50(9H, m), 9.76(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-[(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that the compound(A) obtainedfrom Step 1 was used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-1,5-benzodiazepine,to thereby obtain the title compound(A1).

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.70-2.30(4H, m), 2.61(3H, s),3.36-3.50(1H, m), 3.56-3.68(1H, m), 3.80-3.98(2H, m), 4.47(1H, d),4.55-4.72(2H, m), 4.95(1H, d), 5.15(1H, d), 5.63(1H, d), 5.86(1H, d),7.06-7.50(12H, m), 7.84(1H, d)

Furthermore, the title compound(B1) was obtained, by using the compound(B) obtained from Step 1, in a similar manner as above.

¹H-NMR(DMSO-d₆) δ: 1.34(9H, s), 1.50-1.95(4H, m), 2.42(3H, s),3.26-3.62(3H, m), 4.12-4.40(2H, m), 4.47-4.64(1H, m), 4.78-5.00(1H, m),5.08(2H, d), 5.37(1H, d), 6.85(1H, d), 7.04-7.16(1H, m), 7.22-7.60(10H,m), 7.73(1H, d), 7.93(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-[(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that the compound(A1) obtainedfrom Step 2 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 56, to therebyobtain the title compound(A2).

¹H-NMR(DMSO-d₆, 100° C.) δ: 1.70-2.13(4H, m), 2.45(3H, s), 3.36-3.49(2H,m), 3.64-4.12(2H, m), 4.30-4.70(3H, m), 4.92-5.10(2H, m), 5.32(2H, s),5.40-5.70(1H, br), 6.56(1H, d), 7.20-7.80(21H, m), 8.00(1H, brs),8.90(1H, brs)

Furthermore, the title compound (B2) was obtained, by using the compound(B1) obtained from Step 2, in a similar manner as above.

¹H-NMR(DMSO-d₆) δ: 1.53-1.95(4H, m), 2.44(3H, s), 3.25-3.77(3H, m),4.17-4.65(3H, m), 4.86-5.13(3H, m), 5.32(2H, s), 5.47(1H, d), 6.72(1H,d), 6.86(1H, d), 7.15(1H, t), 7.28-7.63(17H, m), 7.75(1H, d),7.93-8.00(1H, m), 8.03-8.07(1H, m), 9.11(1H, d)

Step 4

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(pyrrolidin-2-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 5 of Example 31 was repeated except that the compound(A2) obtainedfrom Step 3 was used instead of1-[1-[N-(1-methylpiperidin-4-yl)]carbamoylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea,to thereby obtain the title compound(A3).

Melting point: 225-230° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.75-2.40(5H, m), 2.44(3H, s), 3.05-3.50(1H, m),3.66-3.83(2H, m), 4.53-4.73(2H, m), 5.27(1H, d), 5.36(1H, d), 6.98(1H,d), 7.28-7.74(10H, m), 7.90-8.05(2H, m), 8.83(1H, br), 9.24(1H, brs),9.48(1H, br), 12.80(1H, br)

MS(FAB)m/z: 570(MH)⁺

Furthermore, the title compound(B3) was obtained, by using the compound(B2) obtained from Step 3, in a similar manner as above.

Melting point: 219-224° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.43-1.91(4H, m), 2.43(3H, s), 3.10-3.20(2H, m),3.84(1H, dd), 4.27(1H, t), 4.42(1H, t), 4.56-4.70(1H, m), 5.07(1H, d),5.42(1H, d), 6.92(1H, d), 7.27-7.78(10H, m), 7.91-8.04(2H, m),9.00-10.00(3H, br), 11.50-12.50(1H, br)

MS(FAB)m/z: 570(MH)⁺

Example 68

Preparation of1-[1-[N-(tetrazol-5-yl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 1

Preparation of1-[1-benzyloxycarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

Step 3 of Example 1 was repeated except that the1-benzyloxycarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 1 of Example 54 was used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 4 of Example 1, to therebyobtain the title compound.

Melting point: 136-140° C.

¹H-NMR(CDCl₃) δ: 1.00(9H, s), 2.30(3H, s), 3.91(1H, d), 3.95(1H, dd),4.34(1H, t), 4.65-4.78(1H, m), 5.03(1H, d), 5.21(2H, s), 6.06(1H, d),6.83(1H, d), 7.04-7.47(13H, m)

MS(FAB)m/z: 543(MH)⁺

Step 2

Preparation of[3-(3-methylphenyl)ureido-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-1-yl]aceticacid

Step 4 of Example 30 was repeated except that the1-[-1-benzyloxycarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H--1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)ureawas used instead of1-[1-(N-phenyl-N-benzyloxyethylcarbamoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-carboxypbenyl)urea,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.98(9H, s), 2.22(3H, s), 3.85(1H, dd), 4.35(2H, dd),4.53(1H, t), 4.70-4.84(1H, m), 6.33-6.45(1H, m), 6.72-6.82(1H, m),7.00-7.16(3H, m), 7.23-7.36 (4H, m), 7.40-7.50(1H, m), 7.80(1H, brs)

Step 3

Preparation of1-[]-[N-(tetrazol-5-yl)carbamoylmethyl]-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methylphenyl)urea

5-Aminotetrazole (104 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg)were added to a solution of[3-(3-methylphenyl)ureido-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-1-yl]aceticacid (306 mg) in anhydrous methylene chloride (20 ml), the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography (chloroform:methanol=l0:1), the mixed solventof isopropylether and ethanol was added, solidified, and filtrated, toobtain 115 mg of the title compound as a white solid.

¹H-NMR(DMSO-d₆, 100° C.) δ: 0.97(9H, s), 2.21(3H, s), 3.71(1H, dd),4.19(1H, d), 4.20(1H, dd), 4.50(1H, ddd), 5.08(1H, d), 6.49(1H, d),6.66-6.73(1H, m), 7.00-7.17(3H, m), 7.33-7.58(4H, m), 8.53(1H, brs

MS(FAB)m/z: 558(M+K)⁺

Example 69

Preparation of3-[3-(1-phenacyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-phenacyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that 2-bromoacetophenone wasused instead of 2-bromo-2′-methylacetophenone, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 1.40(9H, s), 3.98(1H, dd), 4.27(1H, dd),4.56(1H, d), 4.56-4.61(1H, m), 5.52(1H, d), 5.74(1H, d), 7.22-7.43(4H,m), 7.49-7.55(2H, m), 7.61-7.67(1H, m), 8.01-8.05(2H, m)

Step 2

Preparation of1-(1-phenacyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-phenacyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 1.06(9H, s), 1.35(3H, t), 3.98(1H, dd), 4.29-4.43(1H,m), 4.59(1H, d), 4.88(1H, ddd), 5.75(1H, d), 6.22(1H, d), 7.20-7.66(1H,m), 7.91(1H, s), 7.98(2H, d)

Step 3

Preparation of3-[3-(1-phenacyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-(1-phenacyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.10(9H, s), 4.17(1H, dd), 4.43(1H, dd), 4.67(1H, d),4.80-4.84(1H, m), 5.71(1H, d), 7.23-8.33(16H, m)

MS(FAB)m/z: 543(MH)⁺

Example 70

Preparation of(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea

Diphenylphosphoryl azide (1.1 g) and triethylamine (0.62 ml) were addedto a solution of isophthalic acid mono-benzyl ester (792 mg) in dioxane(20 ml), the mixture was stirred internal temperature at 60° C. for 20minutes and internal temperature at 80° C. for 2 hours. After thereaction mixture was allowed to cool to room temperature, a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(723 mg) obtained from Step 1 of Example 33 in dioxane (5 ml) was addedto the reaction mixture. The reaction mixture was stirred at roomtemperature for 30 minutes. The mixture was concentrated under reducedpressure, chloroform (50 ml) was added to the resultant residue, andwashed with saturated aqueous sodium bicarbonate. After dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, the mixed solvent of isopropyl ether and ethyl acetate wasadded to the residue for trituration, to thereby obtain 674 mg of thetitle compound as a colorless solid (Yield: 54%).

¹H-NMR(CDCl₃) δ: 1.22(9H, s), 3.77(1H, dd), 4.19(1H, dd), 4.50(1H, d),4.85-4.95(1H, m), 5.07(1H, d), 5.32(2H, s), 6.26(1H, d), 6.76-7.67(18H,m), 7.93(1H, s)

Step 2

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Methanol (20 ml) and 10% palladium carbon (68 mg) were added to1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea(635 mg), the mixture was stirred at 50° C. under hydrogen atmospherefor 2 hours. The reaction mixture was filtrated, the filtrate wasconcentrated under reduced pressure. The residue was dissolved in 2 Naqueous sodium hydroxide, washed with ether, adjusted to pH 2 withconcentrated hydrochloric acid, and extracted with chloroform. Theorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under the pressure, the mixed solvent of isopropyl etherand ethyl acetate was added to the residue for trituration, andcollected by filtration, to thereby obtain 144 mg of the title compoundas a colorless solid.

Melting point: 237° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.29(9H, s), 3.72(1H, dd), 4.32(1H, d), 4.43(1H, dd),4.81-4.90(1H, m), 5.23(1H, d), 7.13-8.41(13H, m), 7.50(1H, d), 8.29(1H,s), 10.71-10.77(1H, br)

MS(FAB)m/z: 515(MH)⁺

Step 3

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-tert-butoxycarbonylamino-3-phenylpropionyl)amino]-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-tert-Butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(3.62 g) was dissolved in anhydrous N,N-dimethyl formamide (30 ml) underargon atmosphere, N-tert-butoxycarbonyl-L-phenylalanine (3.00 g),1-hydroxybenzotriazole (1.73 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.17 g) andtriethylamine (2.08 g) were added at ice-cooling, thereto the mixturewas stirred for 5 minutes under ice-cooling, and stirred at roomtemperature for one hour. Water and ethyl acetate were added to thereaction mixture, separated, the organic layer was successively washedwith water and saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 6.17 g of the title compound.

¹H-NMR(CDCl₃) δ: 1.25 and 1.26(9H, each s), 1.41(9H, s), 3.03(2H, br),3.14-3.22 and 3.43-3.50(1H, each m), 4.00-4.50(4H, m), 4.73-4.82(1H, m),4.98(1H, br), 5.10(1H, d), 6.65-6.95(4H, m), 7.06-7.37(10H, m)

Step 4

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionylamino]-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-2-tert-butoxycarbonylamino-3-phenylpropionylamino]-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(6.17 g) was dissolved in 4N HCl-dioxane (30 ml), the mixture wasstirred at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure, saturated aqueous sodiumbicarbonate and ethyl acetate were added to the residue, separated, theorganic layer was successively washed with water and saturated brine,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate saturated with water), separated intocompound(A) of first eluent and compound (B) of second eluent andpurified, to thereby obtain 2.29 g of the title compound(A) and 2.48 gof title compound (B).

Physiochemical data of (A)

¹H-NMR(CDCl₃) δ: 1.25(9H, s), 1.53(2H, br), 2.78(1H, dd), 3.20(1H, dd),3.48(1H, dd), 3.62(1H, dd), 4.19(1H, dd), 4.32(1H, d), 4.81-4.91(1H, m),5.13(1H, d), 6.77(2H, d), 6.87(1H, t), 7.09-7.38(11H, m), 8.14(1H, d)

Physiochemical data of (B)

¹H-NMR(CDCl₃) δ: 1.26(9H, s), 1.63(2H, br), 2.67(1H, dd), 3.21(1H, dd),3.43(1H, dd), 3.58(1H, dd), 4.23(1H, m), 4.33(1H, d), 4.79-4.89(1H, m),5.13(1H, d), 6.76(2H, d), 6.87(1H, t), 7.09-7.36(11H, m), 7.87(1H, d)

Step 5

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-2-(N-phenylthioureido)-3-phenylpropionylamino]-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

The compound (A, 2.29 g) obtained from Step 4 was dissolved in anhydrousmethylene chloride (20 ml), phenyl isothiocyanate (1.21 g) was addeddropwise, the mixture was stirred at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure, the residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 2.91 g of the title compound(A1).

¹H-NMR(CDCl₃) δ: 1.27(9H, s), 3.17(2H, d), 3.55(1H, dd), 4.16-4.29(2H,m), 4.71-4.77(1H, m), 5.12-5.22(2H, m), 6.68-6.89(5H, m), 7.04-7.36(18H,m), 7.83(1H, s)

Furthermore, the title compound (B1) was obtained, by using the compound(B) obtained from Step 4, in a similar manner as above.

¹H-NMR(CDCl₃) δ: 1.23(9H, s), 2.95(1H, dd), 3.14(1H, dd), 3.41(1H, dd),3.97(1H, dd), 4.25(1H, d), 4.67-4.77(1H, m), 5.08(1H, d), 5.15-5.23(1H,m), 6.45(1H, d), 6.68-6.76(4H, m), 6.88(1H, t), 7.04-7.40(18H, m),7.78(1H, s)

Step 6

Preparation of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

The compound (A1, 2.91 g) obtained from Step 5 was dissolved intrifluoroacetic acid (30 ml), and stirred at 50-60 ° C. for 30 minutes.The reaction mixture was concentrated under reduced pressure, saturatedaqueous sodium bicarbonate and ethyl acetate were added to the residue,separated, and extracted with ethyl acetate. The organic layer wassuccessively washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 0.85 g of the titlecompound. Optical purity was 99%ee by HPLC analysis.

[α] D²⁵ (C=1, MeOH): +87°

Step 7

Preparation of(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

The compound (B1, 3.15 g) obtained from Step 5 was dissolved intrifluoroacetic acid (30 ml), stirred at 50-60° C. for 30 minutes. Thereaction mixture was concentrated under reduced pressure, saturatedaqueous sodium bicarbonate and ethyl acetate were added to the residue,separated, the organic layer was washed with water and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography (chloroform:methanol=20:1), to thereby obtain 0.83 g ofthe title compound. Optical purity was 99%ee by HPLC analysis.

[α] D²⁵ (C=1, MeOH): −89°

Step 8

Preparation of(+)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1 was repeated by using(+)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 6. Subsequently, the resultant compound was dissolvedin tetrahydrofuran, palladium carbon was added, the mixture was stirredat room temperature under hydrogen atmosphere for 8 hours. Palladiumcarbon was removed by filtration, the filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (chloroform:methanol=20:1), to thereby obtain the titlecompound. Optical purity was 99.4%ee by HPLC analysis.

[α] D²⁵ (C=1, MeOH): +147.1°

Step 9

Preparation of(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 8 was repeated by using(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 7, to thereby obtain the title compound. Opticalpurity was 99%ee by HPLC analysis.

[] D²⁵ (C=1, MeOH): −134.8°

Example 71

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylphenyl)urea

Step 1 of Example 43 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 1 of Example 33 was used instead of1-(2-toluoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Melting point: 266-267° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.24(9H, s), 2.28(3H, s), 3.65(1H, dd), 4.27(1H, dd),4.40(1H, d), 4.88(1H, dt), 5.11(1H, d), 6.07(1H, d), 6.63(1H, s),6.77-7.25(13H, m)

IR(KBr)cm⁻¹: 3372, 2971, 1717, 1684, 1659, 1593, 1553, 1497, 1426, 1296,1237, 776, 760, 747, 691

MS(FAB)m/z: 485(MH)⁺

Example 72

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]phenylaceticacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonylmethylphenyl)urea

Step 3 of Example 10 was repeated except that methyl(3-aminophenyl)acetate was used instead of ethyl 3-aminobenzoate, andthat1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 56 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 2.51(3H, s), 3.53(2H, s), 3.65(3H, s),4.01(1H, dd), 4.36(1H, dd), 4.43(1H, d), 4.77-4.84(1H, m), 5.50(1H, d),6.09(1H, brs), 6.88-7.68(13H, m)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]phenylaceticacid

Step 4 of Example 10 was repeated except that1-[1-(2-toluoylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonylmethylphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 2.50(3H, s), 3.56(2H, s), 3.98(1H, dd),4.34(1H, dd), 4.53(1H, d), 4.82(1H, dt), 5.43(1H, d), 6.52-7.69(14H, m),12.00-13.00(1H, br)

IR(KBr)cm⁻¹:2971, 1700-1620, 1597, 1561, 1499, 1458, 1397, 1320, 1223,758

MS(FAB)m/z: 571(MH)⁺

Example 73

Preparation of4-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-methoxycarbonylphenyl)urea

Step 3 of Example 10 was repeated except that methyl 4-aminobenzoate wasused instead of ethyl 3-aminobenzoate and that1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 56 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 2.48(3H, s), 3.85(3H, s), 3.98(1H, dd),4.38(1H, dd), 4.39(1H, d), 4.83-4.87(1H, m), 5.55(1H, d), 6.45(1H, d),7.16-7.49(9H, m), 7.63(1H, d), 7.69(1H, brs), 7.84(2H, d)

Step 2

Preparation of4-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-methoxycarbonylphenyl)ureawas used instead of1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 231-233° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.95(9H, s), 2.44(3H, s), 3.72(1H, dd), 4.28(1H, dd),4.50-4.54(1H, m), 4.90(1H, d), 5.46(1H, d), 6.82(1H, d), 7.33-7.60(9H,m), 7.79(2H, d), 7.88(1H, d), 9.19(1H, s), 12.51(1H, brs)

IR(KBr)cm⁻¹:3355, 1719, 1671, 1617, 1597, 1541, 1499, 1418, 1325, 1291,1219, 1173, 774, 752

MS(FAB)m/z: 557(MH)⁺

Example 74

Preparation of3-[3-(1-tert-butoxycarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 50 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 2 of Example 50, to therebyobtain the title compound.

Step 2

Preparation of1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 16 was repeated except that1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butoxycarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Step 3

Preparation of1-(1-tert-butoxycarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea

Step 1 of Example 70 was repeated except that1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 1.46(9H, s), 3.80(1H, d), 3.97(1H, dd),4.37(1H, t), 4.65-4.73(1H, m), 5.14(1H, d), 5.40(2H, s), 6.30(1H, d),7.25-7.53(10H, m), 7.64-7.76(2H, m), 7.95-7.97(1H, m), 8.09(1H, s)

Step 4

Preparation of3-[3-(1-tert-butoxycarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Methanol (20 ml) and 10% palladium carbon (57 mg) were added to1-(1-tert-butoxycarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea(550 mg), the mixture was stirred at room temperature under hydrogenatmosphere for one hour. The reaction mixture was filtrated and thefiltrate was concentrated under reduced pressure. Isopropyl ether wasadded to the residue for trituration and collected by filtration, tothereby obtain 420 mg of the title compound as a colorless solid.

Melting point: 175° C. (decomposition)

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.51(9H, s), 3.93(1H, d), 4.11(1H, dd),4.41(1H, dd), 4.66-4.73(1H, m), 4.77(1H, d), 7.24-8.34(10H, m),10.00-11.00(1H, br)

IR(KBr)cm⁻¹:2980, 1676, 1617, 1595, 1557, 1501, 1395, 1368, 1321, 1225,1156, 754

MS(FAB)nm/z: 539(MH)⁺

Example 75

Preparation of3-[3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-bromo-N-phenyl-N-methylacetamide was used instead of 2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.90(9H, s), 1.39(9H, s), 3.36(3H, s), 3.60(1H, d),3.93(1H, dd), 4.15(1H, dd), 4.70(1H, d), 5.53(1H, d), 6.68-7.54(9H, m)

Step 2

Preparation of1-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-etboxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 1.35(3H, t), 3.31(3H, s), 3.70(1H, d), 3.96(1H, dd),4.31(2H, q), 4.34(1H, dd), 4.72-4.81(2H, m), 6.27(1H, d), 7.21-7.94(14H,m)

Step 3

Preparation of3-[3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 233-237° C. (decomposition)

H-NMR(DMSO-d₆) δ: 0.83(9H, s), 3.24(3H, s), 3.65(1H, dd), 3.90-4.53(3H,m), 4.16(1H, dd), 6.66(1H, d), 7.28-7.56(12H, m), 7.96(1H, s), 9.03(1,s), 12.35-12.90(1H, br)

IR (KBr)cm⁻¹:3366, 1684,1647, 1595, 1565, 1497, 1399, 1323, 1248, 1229,772, 758, 702

MS(FAB) m/z: 572(MH)⁺

Example 76

Preparation of3-[3-(1-methyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-methyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that methyl iodide was usedinstead of 2-bromo-2′-methylacetophenone, to thereby obtain the titlecompound.

¹H-NMR(CDCl₃) δ: 0.99(9H, s), 1.40(9H, s), 3.40(3H, s), 3.83(1H, dd),4.22(1H, dd), 4.36-4.46(1H, m), 5.45(1H, d), 7.20-7.47(4H, m)

Step 2

Preparation of1-(1-methyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-methyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 1.37(3H, t), 3.45(3H, s), 3.93(1H, dd),4.30-4.39(3H, m), 4.65-4.75(1H, m), 6.18(1H, d), 7.26-7.92(9H, m)

Step 3

Preparation of3-[3-[1-methyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-(1-methyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 246° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.92(9H, s), 3.33(3H, s), 3.63(1H, dd), 4.23(1H, dd),4.32-4.39(1H, m), 6.69(1H, d), 7.31(1H, t), 7.38-7.51(4H, m), 7.58(2H,d), 7.99(1H, s), 9.00(1H, s), 12.78(1H, brs)

MS(FAB)m/z: 439(MH)⁺

Example 77

Preparation of3-[3-[1-(2-aminophenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2-nitrophenacyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(100 mg) was added to a suspension of 60% sodium hydride (22 mg) inN,N-dimethylformamide (5 ml), the mixture was stirred at roomtemperature for 15 minutes. Subsequently, 2-bromo-2′-nitroacetophenone(102 mg) was added thereto, and stirred at room temperature for onehour. Water was added to the reaction mixture, extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. Isopropyl ether was added to the residue fortrituration and collected by filtration, to thereby to obtain 76 mg ofthe title compound as a light yellow solid (Yield: 52%).

¹H-NMR(CDCl₃) δ: 0.98(9H, s), 1.41(9H, s), 3.95(1H, dd), 4.29(1H, dd),4.57(1H, d), 4.52-4.63(1H, m), 5.28(1H, d), 5.46(1H, brd), 7.26-8.23(8H,m)

Step 2

Preparation of1-[1-(2-nitrophenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-(2-nitro)phenacyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 1.07(9H, s), 1.36(3H, t), 4.02(1H, dd), 4.30-4.49(4H,m), 4.80-4.90(1H, m), 5.19(1H, d), 6.14(1H, brd), 7.26-7.68(11H, m),7.91(1H, s), 8.12(1H, d)

Step 3

Preparation of1-[1-(2-aminophenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Etanol (20 ml) and 10% palladium carbon (70 mg) were added to1-[1-(2-nitrophenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(700 mg), the mixture was stirred at room temperature under hydrogenatmosphere for 3 hours. The reaction mixture was filtrated and thefiltrate was concentrated under reduced pressure, to thereby to obtain280 mg of the title compound as colorless oil.

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 1.35(3H, t), 3.98(1H, dd), 4.32(2H, q),4.39(1H, dd), 4.57(1H, d), 4.86-4.96(1H, m), 5.75(1H, d), 6.26(2H, brs),6.30(1H, brd), 6.62-6.68(2H, m), 7.12(1H, s), 7.16-7.91(10H, m)

Step 4

Preparation of3-[3-[1-(2-aminophenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(2-aminophenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.08(9H, s), 4.16(1H, dd), 4.43(1H, dd), 4.65(1H, d),4.79-4.89(1H, m), 5.70(1H, d), 6.67-6.73(2H, m), 7.19-7.70(10H, m),8.15(1H, s), 8.29(1H, d)

MS(FAB)m/z: 558(MH)⁺

Example 78

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]phenylthioaceticacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea

Step 2 of Example 33 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 56 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 1.93(3H, t), 2.49(3H, s), 3.61(2H, s),3.99(1H, dd), 4.13(2H, q), 4.37(1H, t), 4.40(1H, d), 4.79-4.87(1H, m),5.51(1H, d), 6.28(1H, d), 6.96-7.48(12H, m), 7.64(1H, d)

Step 2

Preparation of3-[3-(1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]phenylthioaceticacid

Step 3 of Example 33 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylmethylthiophenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea,to thereby obtain the title compound.

Melting point: 127-130° C.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 2.47(3H, s), 3.52(2H, ABq), 3.89(1H, dd),4.41(1H, t), 4.53(1H, d), 4.77-4.88(1H, m), 5.06(1H, brs), 5.51(1H, d),6.52(1H, d), 6.91-7.74(13H, m)

MS(FAB)m/z: 603(MH⁺)

Example 79

Preparation of3-[3-[1-(2-methoxyphenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2methoxyphenacyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-bromo-2′-methoxyacetophenone was used instead of2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 1.40(9H, s), 3.92(3H, s), 3.93-4.02(1H,m), 4.26(1H, dd), 4.57(1H, d), 4.50-4.58(1H, m), 5.56(1H, d),5.52-5.56(1H, brs), 6.99-7.58(7H, m), 7.98(11H, dd)

Step 2

Preparation of1-[1-(2-methoxyphenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-(2-methoxyphenacyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(CDCl₃) δ: 1.06(9H, s), 1.35(3H, t), 3.87(3H, s), 4.33(2H, q),4.32(1H, dd), 4.38(1H, dd), 4.61(1H, d), 4.58-4.89(1H, m), 5.59(1H, d),6.31(1H, d), 6.95(1H, d), 6.99-7.94(12H, m)

Step 3

Preparation of3-[3-[1-(2-methoxyphenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that3-[3-[1-(2-methoxyphenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid was used instead of1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 0.96(9H, s), 3.67-3.75(1H, m), 4.27(1H, dd),4.48-4.57(1H, m), 4.71(1H, d), 5.40(1H, d), 6.67(1H, d), 7.06-7.12(1H,m), 7.23(1H, d), 7.28-7.65(8H, m), 7.77(1H, dd), 7.99(1H, s), 9.00(1H,s), 12.70(1H, brs)

MS(FAB)m/z: 573(MH)⁺

Example 80

Preparation of3-[3-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea

Step 3 of Example 56 was repeated except that1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 16 was used instead of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.36(9H, s), 3.61(1H, dd), 3.96-4.08(1H, m),4.39-4.63(3H, m), 5.32(2H, s), 6.66-6.87(4H, m), 7.13-7.61(14H, m),8.04-8.08(1H, m), 9.17(1H, s)

Step 2

Preparation of3-[3-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 5 of Example 31 was repeated except that1-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)ureawas used instead of1-[1-(1-methylpiperidin-4-yl)carbamoylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 215-216° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.36(9H, s), 3.63(1H, dd), 4.01(1H, dd),4.40-4.64(3H, m), 6.70-6.88(4H, m), 7.13-7.57(9H, m), 8.02(1H, d),9.12(1H, s), 12.50-13.20(1H, br)

MS(FAB)m/z: 531(MH)⁺

Example 81

Preparation of3-[3-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]phenylthioaceticacid

Step 1

Preparation of1-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylmethylthiophenyl)urea

Triphosgene (1.06 g) was added to a solution of benzyl3-aminophenylthioacetate (2.06 g) in anhydrous tetrahydrofuran (100 ml)at 0° C., triethylamine (0.45 ml) was added thereto, and the mixture wasstirred at same temperature for 10 minutes. A solution of1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(3.92 g) obtained from Step 2 of Example 16 in anhydrous tetrahydrofuran(50 ml) was added, the mixture was stirred at room temperature for onehour. The reaction mixture was concentrated under reduced pressure,water (200 ml) was added to the residue, and the resultant mixture wasextracted with methylene chloride. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=2:1),isopropyl ether was added to the solid so precipitated for trituration,collected by filtration, to thereby obtain 4.60 g of the title compoundas a white solid (Yield: 84.4%).

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 3.66(2H, s), 3.63-3.74(1H, m), 4.21(1H,d), 4.22(1H, d), 4.64(1H, d), 4.86(1H, ddd), 5.12(2H, s), 6.19(1H, d),6.72-7.40(19H, m)

MS(FAB)m/z: 667(MH)⁺

Step 2

Preparation of3-[3-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]phenylthioaceticacid

Aqueous solution (15 ml) of lithium hydroxide (57 mg) was added to asolution of1-[1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylmethylthiophenyl)urea(864 mg) in tetrahydrofuran (45 ml), the mixture was stirred at roomtemperature for 5 hours. The reaction mixture was concentrated underreduced pressure, the residue was adjusted to pH 2 with 1N hydrochloricacid, and extracted with methylene chloride. The organic layer was driedover anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure, the residue was purified by silica gel columnchromatography (chloroform:methanol=5:1), the mixed solvent of isopropylether and ethanol was added to the solid so precipitated fortrituration, collected by filtration, to thereby obtain 177 mg of thetitle compound as white powder.

¹H-NMR(DMSO-d₆) δ: 1.36(9H, s), 3.53(2H, s), 3.55-3.68(1H, m), 3.97(1H,dd), 4.43(1H, d), 4.52(1H, d), 4.52-4.62(1H, m), 6.73-6.87(4H, m),6.92(1H, d), 7.02-7.46(9H, m), 9.11(1H, s)

MS(FAB) m/z : 559(MH-H₂O)⁺

Example 82

Preparation of(−)-3-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride and(+)-3-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

Step 1

Preparation of(−)-2-oxo-3-tert-butoxycarbonylamino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineand(+)-2-oxo-3-tert-butoxycarbonylamino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 60 was repeated except that(N-benzyloxycarbonyl)-L-proline was used instead of(N-benzyloxycarbonyl)pipecholinic acid. The resultant crude product waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1), to thereby obtain(−)-2-oxo-3-tert-butoxycarbonylamino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(A)of first eluent and(+)-2-oxo-3-tert-butoxycarbonylamino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(B)of second eluent.

Physiochemical data of (A)

[α] D²⁴ (C=0.40, CHCl₃): −65.6°

Physiochemical data of (B)

[α] D²⁴ (C=0.42, CHCl₃): +113.9°

Step 2

Preparation of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 10 was repeated except that the compound(A) obtainedfrom Step 1 was used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-1,5-benzodiazepine,to thereby obtain(+)-1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-[(2S)-(N-benzytoxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(A1).

¹H-NMR(DMSO-d₆, 100° C.) δ: 1.50-1.70(9H, m), 1.78(9H, s), 2.10-2.55(4H,m), 3.80-4.05(3H, m), 4.24-4.82(3H, m), 4.90-5.10(1H, m), 5.40-5.80(3H,m), 6.98(1H, d), 7.60-8.00(9H, m)

[α] D²³ (C=0.50, CHCl₃): +9.3°

Furthermore,(+)-1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(B1)was obtained, by using the compound (B) obtained from Step 1, in asimilar manner as above.

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.34(9H, s), 1.50-1.94(4H, m),3.33-3.53(3H, m), 4.14-4.54(4H, m), 5.00-5.13(3H, m), 6.50-6.65(1H, m),7.16-7.52(9H, m)

[α] D²⁵ (C=0.50, CHCl₃): +71.5°

Step 3

Preparation of(−)-1-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)ureaand(+)-1-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that the compound(A1) obtainedfrom Step 2 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4t5-tetrahydro-2H-1,5-benzodiazepineto thereby obtain1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, Step 3 of Example 56 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-[(2S)-(N-benzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineand that benzyl isophtalate was used instead of 3-aminobenzoic acid, tothereby obtain(−)-1-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea(A2).

¹H-NMR(DMSO-d₆, 100° C.) δ: 1.16(9H, brs), 1.70-2.10(4H, m),3.37-3.48(2H, m), 3.65-4.62(5H, m), 5.04(1H, d), 5.08(1H, d),5.20-5.40(1H, br), 5.32(2H, s), 6.52(1H, d) 7.15-7.60(17H, m), 7.99(1H,t), 8.89(1H, s)

[α] D²⁷ (C=0.51, CHCl₃): −22.0°

Furthermore,(+)-1-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea(B2) was obtained, by using the compound (B1) obtained from Step 2, in asimilar manner as above.

¹H-NMR(DMSO-d₆, 100° C.) δ: 1.20(9H, s), 1.55-1.94(4H, m), 3.35-3.48(2H,m), 3.60-3.74(1H, m), 4.24-4.36(2H, m), 4.42-4.55(2H, m), 5.09(2H, s),5.10(1H, d), 5.32(2H, s), 6.51(1H, d), 7.16-7.60(17H, m), 7.99(1H, t),8.86(1H, s)

[α] D²⁷ (C=0.52, CHCl₃): +72.4°

Step 4

Preparation of(−)-3-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride and(+)-3-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

Step 5 of Example 31 was repeated except that the compound(A2) obtainedfrom Step 3 was used instead of1-[1-N-(1-methylpiperidin-4-yl)]carbamoylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea,to thereby obtain(−)-1-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-carboxyphenyl)ureahydrochloride(A3).

¹H-NMR(DMSO-d₆) δ: 1.17(9H, s), 1.74-2.20(4H, m), 3.00-3.78(4H, m),4.46-4.66(2H, m), 4.88(1H, d), 5.02(1H, d), 6.89(1H, d), 7.28-7.37(1H,m), 7.40-7.69(6H, m), 8.00(1H, t), 8.60-9.80(2H, br), 9.16(1H, brs)

[α] D²⁴ (C=0.50, MeOH): −10.7°

MS(FAB)m/z: 536(MH)⁺

Furthermore,(+)-3-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-[(2S)-pyrrolidin-2-yl]carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride(B3) was obtained, by using the compound(B2) obtainedfrom Step 3, in a similar manner as above.

¹H-NMR(DMSO-d₆) δ: 1.19(9H, s), 1.40-1.91(4H, m), 3.10-3.20(2H, m),3.80(1H, dd), 4.23(1H, t), 4.36(1H, t), 4.48-4.64(1H, m), 4.66(1H, d),5.09(1H, d), 6.86(1H, d), 7.28-7.37(2H, m), 7.45-7.55(3H, m),7.58-7.74(2H, m), 8.01(1H, t), 8.70-9.80(2H, br), 9.23(1H, brs),12.00-13.00(1H, br)

[α] D²⁴ (C=0.50, MeOH): +18.9°

MS(FAB)m/z: 536(MH)⁺

Example 83

Preparation of4-[3-[1-(furan-2-yl)carbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(furan-2-yl)carbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 15 was repeated except that 2-bromoacetylfuran wasused instead of 2-bromo-(N-phenyl-N-methyl)acetamide, to thereby obtainthe title compound.

¹H-NMR(CDCl₃) δ: 3.60-3.70(1H, m), 4.25(1H, dd), 4.63-4.78(1H, m),4.84(1H, d), 5.08(2H, s), 5.34(1H, d), 5.88(1H, d), 6.53(1H, dd),6.76(2H, d), 6.87(1H, t), 7.15-7.40(12H, m), 7.56(1H, d)

Step 2

Preparation of1-(furan-2-yl)carbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 15 was repeated except that1-(furan-2-yl)carbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methylcarbamoylmethyl)-2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Step 3

Preparation of1-[1-(furan-2-y1)carbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea

Step 1 of Example 81 was repeated except that1-(furan-2-yl)carbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineand that ethyl 4-aminobenzoate was used instead of ethyl3-aminophenylthioacetate, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.37(3H, t), 3.73(1H, dd), 4.19(1H, dd), 4.32(2H, q),4.93(1H, d), 4.91-5.03(1H, m), 5.35(1H, d), 6.48-6.56(2H, m),6.74-6.90(3H, m), 7.12-7.37(9H, m), 7.55-7.65(2H, m), 7.78-7.90(2H, m)

Step 4

Preparation of4-[3-[1-(furan-2-yl)carbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(furan-2-yl)carbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)ureawas used instead of1-(tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 3.63(1H, dd), 4.04(1H, dd), 4.63(1H, ddd), 5.10(1H,d), 5.36(1H, d), 6.73(1H, dd), 6.78-6.90(4H, m), 7.13-7.37(5H, m),7.40-7.49(3H, m), 7.61(1H, d), 7.80(2H, d), 8.03(1H, d), 9.27(1H, s),12.40-12.60(1H, br)

MS(FAB)m/z: 525(MH)⁺

Example 84

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(piperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(N-benzyloxycarbonylpiperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 60 was repeated except that(N-benzyloxycarbonyl)isonipecotic acid was used instead of(N-benzyloxycarbonyl)pipecolinic acid, to thereby obtain the titlecompound.

¹H-NMR(CDCl₃) δ: 1.23-1.95(6H, m), 1.40(9H, s), 2.11-2.68(3H, m),3.80-4.30(3H, m), 4.40-4.63(2H, m), 5.08(2H, s), 5.40-5.48(1H, m),7.13-7.54(9H, m), 7.60-7.73(1H, br)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(N-benzyloxycarbonylpiperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(N-benzyloxycarbonylpiperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.60-1.90(4H, m), 2.32-2.70(3H, m),2.44(3H, s), 3.85(1H, dd), 4.00-4.27(2H, br), 4.43-4.66(2H, m),5.05-5.23(2H, m), 5.10(2H, s), 5.47(1H, d), 7.22-7.49(12H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(N-benzyloxycarbonylpiperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(N-benzyloxycarbonylpiperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 56, to therebyobtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.40-1.90(4H, m), 2.25-2.70(3H, m), 2.37(3H, s),3.65(1H, dd), 3.86-4.06(2H, m), 4.37-4.62(2H, m), 5.04(2H, s), 5.26(1H,d), 5.32(2H, s), 5.37(1H, d), 6.72(1H, d), 7.26-7.62(20H, m), 7.97(1H,d), 8.04(1H, brs), 9.09(1H, s)

Step 4

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(piperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid hydrochloride

Step 5 of Example 31 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-(N-benzyloxycarbonylpiperidin-4-yl)carbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)ureawas used instead of-[1-(1-methylpiperidin-4-yl)carbamoylmethyl-2-oxo-5-pivaolyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 216-226° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.70-2.05(4H, m), 2.37(3H, s), 2.33-2.74(3H, m),3.12-3.38(2H, m), 4.37-4.63(2H, m), 5.33(2H, s), 6.85(1H, d),7.28-7.64(11H, m), 7.96(1H, d), 8.01(1H, t), 8.50-9.00(2H, br), 9.20(1H,brs), 12.60-13.00(1H, br)

MS(FAB)m/z: 584(MH)⁺

Example 85

Preparation of4-[3-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that benzoyl chloride was usedinstead of pivaloyl chloride and that2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Referential Example 4 was used instead of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.27(3H, s), 4.15(1H, dd), 4.32-4.50(1H,m), 4.60-4.73(1H, m), 5.54(1H, d), 6.57-6.80(2H, m), 6.92(1H, s),7.08-7.32(5H, m), 8.08(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-benzoyl1-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 2.27(3H, s), 2.57(3H, s), 4.16(1H, dd),4.28-4.44(1H, m), 4.64-4.86(2H, m), 5.42-5.64(2H, m), 6.58-6.80(2H, m),7.01(1H, s), 7.10-7.52(8H, m), 7.83(1H, d)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, Step 3 of Example 10 was repeated except that ethyl4-aminobenzoate was used instead of ethyl 3-aminobenzoate, to therebyobtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.29(3H, t), 2.27(3H, s), 2.45(3H, s), 3.87-3.98(1H,m), 4.20-4.37(1H, m), 4.25(2H, q), 4.60-4.73(1H, m), 5.18(1H, d),5.52(1H, d), 6.77-7.00(3H, m), 7.15-7.63(11H, m), 7.83(2H, d), 8.03(1H,d), 9.28(1H, brs)

Step 4

Preparation of4-[3-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)ureawas used instead of1-(1-tertbutylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 210-222° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 2.28(3H, s), 2.45(3H, s), 3.85-3.98(1H, m),4.22-4.37(1H, m), 4.67(1H, ddd), 5.18(1H, d), 5.51(1H, d), 6.78-6.92(2H,m), 6.99(1H, d), 7.15-7.56(11H, m), 7.81(2H, d), 8.03(1H, d), 9.28(1H,s), 11.50-12.80(1H, br)

MS(FAB)m/z: 591(MH)⁺

Example 86

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Step 2 of Example 85 was used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.30(3H, t), 2.28(3H, s), 2.46(3H, s), 3.86-3.98(1H,m), 4.22-4.38(1H, m), 4.28(2H, q), 4.60-4.74(1H, m), 5.18(1H, d),5.51(11H, d), 6. 75-6.93(3H, m), 7.16-7.57(12H, m), 8.03(1H, d)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 250-251° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 2.28(3H, s), 2.46(3H, s), 3.85-3.98(1H, m),4.22-4.38(1H, m), 4.67(1H, dt), 5.18(1H, d), 5.51(1H, d), 6.76-6.92(3H,m), 7.15-7.56(12H, m), 7.99-8.07(2H, m), 9.07(1H, s), 12.50-13.00(1H,br)

MS(FAB)m/z: 591(MH)⁺

Example 87

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-cyclopentylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 1 was repeated except that cyclopentylcarbonylchloride was used instead of pivaloyl chloride, and that2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Referential Example 4 was used instead of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.25-1.48(4H, m), 1.41(9H, s), 1.52-1.75(3H, m),1.80-1.95(1H, m), 2.32-2.47(1H, m), 2.39(3H, s), 3.75-3.84(1H, m),4.46-4.65(2H, m), 5.42(1H, d), 6.96(1H, s), 7.05-7.15(2H, m), 7.67(1H,s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbony1-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.30-1.95(8H, m), 1.40(9H, s), 2.38(3H, s),2.45-2.60(1H, m), 2.51(3H, s), 3.75-l 3.85(1H, m), 4.47-4.67(2H, m),4.86(1H, d), 5.21(1H, d), 5.48(1H, d), 7.06(1H, s), 7.08-7.17(2H, m),7.25-7.35(2H, m), 7.39-7.47(1H, m), 7.72-7.77(1H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclopentylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Step 2 of Example 10 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclopentylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine.Subsequently, in a similar manner to Step 3 of Example 10, to therebyobtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.25-1.48(2H, m), 1.30(3H, t), 1.53-1.77(6H, m),2.35-2.53(1H, m), 2.40(6H, s), 3.60(1H, dd), 4.28(2H, q), 4.40-4.63(2H,m), 5.18(1H, d), 5.31(1H, d), 6.72(11H, d), 7.21-7.27(1H, m),7.30-7.41(5H, m), 7.45-7.54(3H, m), 7.95(1H, d), 8.05(1H, t), 9.06(1H,s)

Step 4

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-cyclopentylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 10 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-cyclopentylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 166-183° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.22-1.78(8H, m), 2.30-2.55(1H, m), 2.39(6H, s),3.55-3.65(1H, m), 4.40-4.63(2H, m), 5.18(1H, d), 5.31(1H, d), 6.72(1H,d), 7.21-7.41(6H, m), 7.45-7.54(3H, m), 7.96(1H, d), 8.01(1H, t),9.01(1H, s), 12.60-13.00(1H, br)

MS(FAB)m/z: 583(MH)⁺

Example 88

Preparation of(+)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)]ureido]phenylthioaceticacid and(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)]ureido]phenylthioaceticacid

Step 1

Preparation of(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylthiophenyl)urea

Triphosgene (592 mg) was added to a solution of tert-butyl3-aminophenylthioacetate (1.27 g) in tetrahydrofuran (100 ml) underice-cooling, triethylamine (2.5 ml) was added thereto five times each0.5 ml over 15 minutes, and the mixture was stirred at room temperaturefor 5 minutes. A solution of(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.7 g) obtained from Step 7 of Example 70 in tetrahydrofuran (20 ml)was added to the mixture, stirred at room temperature for one hour. Thereaction mixture was concentrated under reduced pressure, water wasadded to the residue, extracted with methylene chloride. The organiclayer was dried over anhydrous sodium sulfate, the mixture was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=2:1), tothereby obtain 2.75 g of the title compound.

[α] D²⁰ (C=1.05, CHCl₃): −94.7°

¹H-NMR(CDCl₃) δ: 1.24(9H, s), 1.38(9H, s), 3.54(2H, s), 3.68(1H, dd),4.18(1H, dd), 4.40(1H, d), 4.85-4.94(1H, m), 5.17(1H, d), 6.36(1H, d),6.76-7.22(13H, m), 7.44(1H, s)

Step 2

Preparation of(+)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylthiophenyl)urea

Step 1 was repeated except that(+)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

[α] D²⁵ (C=1.03, CHCl₃): +95.8°

Step 3

Preparation of(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)]ureido]phenylthioaceticacid

Trifluoroacetic acid (20 ml) was added to a solution of(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylthiophenyl)urea(2.75 g) in methylene chloride (20 ml), the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure and the resultant residue was purified by silica gelcolumn chromatography (chloroform:methanol=5:1), to thereby obtain 2.5 gof the title compound.

[α] D²⁰ (C=0.62, CHCl₃): −45.8°

Step 4

Preparation of(+)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)]ureido]phenylthioacetic acid

Step 3 was repeated except that(+)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylthiophenyl)ureawas used instead of(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylthiophenyl)urea,to thereby obtain the title compound.

[α] D²⁵ (C=0.50, CHCl₃): +44.0°

The structure of these compounds obtained from Examples 1-88 was shownin Tables 1-12.

TABLE 1

Example R₁ R₂ R₃ R_(p) n 1 H

1 2 H

0 3 H

1 4 8-Me

1 5 8-F

1 6 H

1 7 H

1

TABLE 2

Example R₁ R₂ R₃ R_(p) n  8 H

1  9 H

1 10 H

1 11 H

1 12 H

1 13 8-Me

1 14 H

1

TABLE 3

Example R₁ R₂ R₃ R_(p) n 15 H

1 16 H

1 17 H —CF₃

1 18 H

1 19 H —CH₂OMe

0 20 H H

0 21 H

1 22 H

1

TABLE 4

Example R₁ R₂ R₃ R_(p) n 23 H

1 24 H

1 25 H

1 26 H

1 27 H

—CONMe₂

1 28 H

1 29 H

1 30 H

1

TABLE 5

Example R₁ R₂ R₃ R_(p) n 31  H

1 32 H

1 33 H

1 34 H

1 35 H

1 36 H

1 37 H

1 : monohydrochloride

TABLE 6

Example R₁ R₂ R₃ R_(p) n 38 H

0 39 H

0 40 H —CONH—Bu-t

1 41 H

1 42 H —COOH

1 43 H

1 44 H

Me

1 45 H

1

TABLE 7

Example R₁ R₂ R₃ R_(p) n 46 H

1 47 H

—SO₂Me

1 48 H

1 49 H

—COOMe

1 50 H

1 51 H

1 52 H —CONMe₂

1 53 H

1

TABLE 8

Example R₁ R₂ R₃ R_(p) n 54 H

1 55 H

1 56 (*) H

1 57 H

1 58 H

1 59 H

1 60 H

1 (*): optically active compound

TABLE 9

Example R₁ R₂ R₃ R_(p) n 61 H

1 62 H

1 63 H

1 64 H

1 65 H

1 66  H

1 67  H

1 : monohydrochloride

TABLE 10

Example R₁ R₂ R₃ R_(p) n 68 H

1 69 H

1 70 (*) H

1 71 H

1 72 H

1 73 H

1 74 H

1 75 H

1 (*): optically active compound

TABLE 11

Example R₁ R₂ R₃ R_(p) n 76 H Me

0 77 H

1 78 H

1 79 H

1 80 H

1 81 H

1 82 (*) H

1 : monohydrochloride (*): optically active compound

TABLE 12

Example R₁ R₂ R₃ R_(p) n 83 H

1 84  H

1 85 8-Me

1 86 8-Me

1 87 8-Me

1 88 (*) H

1 : monohydrochloride (*): optically active compound

Referential Example 7

Preparation of2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Potassium carbonate (6.91 g) was added to a solution of3-amino-2-(tert-butoxycarbonyl)aminopropionic acid (5.11 g) obtainedfrom Step 2 of Referential Example 1 and 4-fluoro-3-nitrotoluene (3.88g) in ethanol (100 ml), the mixture was refluxed overnight. The reactionmixture was allowed to cool, filtrated, and the filtrate wasconcentrated under reduced pressure, to thereby obtain3-(2-nitro-4-methyl)anilino-2-tert-butoxycarbonylaminopropionic acid.

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.26(3H, s), 3.55-3.89(2H, m),4.45-4.63(1H, m), 5.44(1H, d), 6.91(1H, d), 7.27(1H, d), 7.94(1H, s),8.14(1H, brs), 11.50(1H, brs)

This obtained compound was dissolved in water (200 ml), washed withdiethyl ether, then adjusted to pH 3 with 1N hydrochloric acid, andextracted with methylene chloride. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and the solventwas evaporated. The residue was dissolved in ethanol (200 ml), 10%palladium carbon (1 g) was added, and the mixture was stirred for 5hours under hydrogen atmosphere, under ambient pressure. The reactionmixture was filtrated, the filtrate was concentrated under reducedpressure, toluene was added and crystals so precipitated were collectedby filtration, to thereby obtain3-(2-amino-4-methylanilino)-2-tert-butoxycarbonylaminopropionic acid.This compound was suspended in toluene (100 ml), the mixture wasrefluxed overnight while water was removed by use of a Dean-Starkcondenser. The reaction mixture was allowed to cool, crystals soprecipitated were collected by filtration, and washed with isopropylether, subsequently, dried, to thereby obtain 1.66 g of the titledcompound (Yield: 40%).

¹H-NMR(DMSO-d₆) δ: 1.36(9H, s), 2.17(3H, s), 3.25-3.32(1H, m),3.43-3.49(1H, m), 4.07-4.18(1H, m), 5.30(1H, d), 6.70-6.76(3H, m),6.83(1H, d), 9.61(1H, s)

Referential Example 8

Preparation of2-oxo-3-benzyloxycarbonylamino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1

Preparation of N-phenyl-2-nitro-4-methoxyaniline2-Nitro-4-methoxyaniline (75 g), bromobenzene (270 ml), potassiumcarbonate (31 g), copper powder (5.0 g) and potassium iodide (2.1 g)were mixed, the mixture was refluxed for 24 hours. The reaction mixturewas allowed to cool. Insoluble products were removed by filtration. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=10:1), to thereby obtain 51 g of the titled compound as dark redcrystals.

¹H-NMR(CDCl₃) δ: 3.82(3H, s), 7.04-7.64(8H, m), 9.33(1H, brs)

Step 2

Preparation of N-phenyl-N-(2-cyanoethyl)-2-nitro-4-methoxyanilineN-phenyl-2-nitro-4-methoxyaniline (51 g) was dissolved in acrylonitrile(250 ml), triton B (40% benzyltrimethylammonium hydroxide in methanolsolution) (1.0 ml) was added, and the mixture was stirred for 5 hours atroom temperature. The reaction mixture was concentrated, the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1), to thereby 39.5 g of the titled compound as orange-yellowcrystals.

¹H-NMR(CDCl₃) δ: 2.77(2H, t), 3.90(3H, s), 4.00(2H, t), 6.51-7.46(8H, m)

Step 3

Preparation of N-phenyl-N-(2-cyanoethyl)-2-amino-4-methoxyaniline

N-Phenyl-N-(2-cyanoethyl)-2-nitro-4-methoxyaniline (39.5 g) wasdissolved in tetrahydrofuran (200 ml), 10% palladium carbon (4.0 g) wasadded, the mixture was stirred for 9 hours under hydrogen atmosphere.Palladium carbon was removed by filtration, the filtrate wasconcentrated under reduced pressure, to thereby obtain 35.6 g of thetitled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 2.67(2H, t), 3.79(3H, s), 3.81(2H, brs), 3.92(3H, t),6.34-7.24(8H, m)

Step 4

Preparation of 3-[N-(2-amino-4-methoxyphenyl)-N-phenyl]aminopropionicacid

N-Phenyl-N-(2-cyanoethyl)-2-amino-4-methoxyaniline (35.6 g) wasdissolved in ethanol (200 ml), a solution (400 ml) of aqueous potassiumhydroxide (71g) was added, the mixture was refluxed for 4 hours. Thereaction mixture was allowed to cool, adjusted to pH 2 with concentratedhydrochloric acid, and extracted with chloroform. The organic layer wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure,to thereby obtain 38.1 g of the titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 2.70(2H, t), 3.78(3H, s), 3.90(2H, t), 5.00(3H, br),6.33-7.21(8H, m)

Step 5

Preparation of2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

3-[N-(2-Amino-4-methoxyphenyl)-N-phenyl]aminopropionic acid (38.1 g) wasdissolved in xylene (500 ml), the solution was refluxed for 20 hourswhile water was removed by use of a Dean-Stark condenser. The reactionmixture was allowed to cool to room temperature, crystals soprecipitated were collected by filtration, to thereby obtain 29.7 g ofthe titled compound (Yield: 83%).

¹H-NMR(CDCl₃) δ: 2.65(2H, t), 3.82(3H, s), 4.00(2H, t), 6.61-6.83(5H,m), 7.13-7.22(2H, m), 7.34(1H, brs)

Step 6

Preparation of1-methoxymethyl-2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere, 60% sodium hydride (1.12 g) was suspended intetrahydrofuran (10 ml), a solution of2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (5.0g) in tetrahydrofuran (50 ml) was added thereto under ice-cooling, andthe mixture was stirred for 40 minutes at same temperature. After icebath was removeded, methoxymethyl chloride (2.25 g) was added, themixture was stirred for 2 hours at room temperature. The reactionmixture was poured into ice-water, extracted with methylene chloride.The organic layer was successively washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=2:1), to therebyobtain 5.05 g of the titled compound as yellow-brown crystals (Yield:87%).

¹H-NMR(CDCl₃) δ: 2.64(2H, br), 3.34(3H, s), 3.83(3H, s), 3.93(2H, br),5.19(2H, brs), 6.73-7.22(8H, m)

Step 7

Preparation of1-methoxymethyl-2-oxo-3-hydroxyimino-5-phenyl-8-methoxy-1,3,4,5-hexahydro-2H-1,5-benzodiazepine

Under argon atmosphere,1-methoxymethyl-2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(5.05 g) was dissolved in toluene (60 ml), under cooling potassiumtert-butoxide (9.09 g) was added, stirred for 30 minutes at sametemperature, tert-butyl nitrite (4.64g) was added thereto, and themixture was stirred for 2 hours and 30 minutes at room temperature.Saturated brine was added to the reaction mixture, extracted with ethylacetate. The organic layer was succesively washed with water andsaturated brine, dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=50:1), to therebyobtain 3.52 g of the titled compound as pale brown amorphous.

¹H-NMR(CDCl₃) δ: 3.43(3H, s), 3.82(3H, s), 4.60(2H, br), 5.20(2H, br),6.73-7.29(9H, m)

Step 8

Preparation of1-methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-Methoxymethyl-2-oxo-3-hydroxyimino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) was dissolved in tetrahydrofuran (10 ml), propyl isocyanate(0.62 g) and triethylamine (0.74 g) were added thereto, the mixture wasrefluxed for 2 hours and 30 minutes. The reaction mixture was allowed tocool to room temperature, crystals so precipitated were collected byfiltration, and the crystals were washed with diisopropyl ether, tothereby obtain 0.78 g of the titled compound as white crystals.

¹H-NMR(CDCl₃) δ: 0.91(3H, t), 1.47-1.60(2H, m), 3.15-3.20(2H, m),3.42(3H, s), 3.82(3H, s), 4.43(1H, br), 4.91(1H, br), 5.21(1H, br),5.32-5.65(1H, br), 6.23-7.27(8H, m)

Step 9

Preparation of1-methoxymethyl-2-oxo-3-amino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-Methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.78 g) was suspended in methanol (20 ml), 10% palladium carbon (0.20g) was added thereto, the mixture was swung for 2 hours and 30 minutesunder hydrogen atmosphere (3.5-3.0 kg/cm²). The palladium carbon wasremoved by filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 0.63 g of the titledcompound.

¹H-NMR(CDCl₃) δ: 1.73(2H, brs), 3.34(3H, s), 3.49-3.81(2H, m), 3.83(3H,s), 3.87-3.92(1H, m), 5.15(1H, d), 5.31(1H, d), 6.70-7.22(8H, m)

Step 10

Preparation of2-oxo-3-benzyloxycarbonylamino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine1-Methoxymethyl-2-oxo-3-amino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(200 mg) was dissolved in 25% hydrobromic acid-acetic acid solution (1ml), the solution was stirred for 2 hours. The reaction mixture wasconcentrated under reduced pressure, diisopropyl ether was added, thesolid so precipitated was collected by filtration. The solid wasdissolved in water (3 ml), a solution of benzyl chloroformate (140 mg)in tetrahydrofuran (3 ml) and 1N aqueous sodium hydroxide (2.8 ml) weresuccessively added, and the mixture was stirred for one hours. Water wasadded to the resultant mixture, extracted with methylene chloride. Theorganic layer was successively washed with water and saturated brine,dried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 107 mg ofthe titled compound as colorless amorphous.

¹H-NMR(CDCl₃) δ: 3.65(1H, m), 3.81(3H, s), 4.16-4.28(1H, m),4.61-4.70(1H, m), 5.09(2H, s), 5.83(1H, brd), 6.63-7.35(13H, m),7.55(1H, brs)

Referential Example 9

Preparation of2-oxo-3-benzyloxycarbonylamino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1

Preparation of N-(2-nitrophenyl)-2-fluoroaniline

2-Nitroaniline (14.9 g), 2-fluoronitrobenzene (29 g), potassiumcarbonate (14.9 g), copper powder (6.9 g) and xylene (100 ml) was mixed,the mixture was refluxed for 39 hours under argon atmosphere. Thereaction mixture was allowed to cool, filtrated, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved ethylacetate, successively washed with water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=10:1), to thereby obtain 18.0 g of the titledcompound as orange color crystals (Yield: 72%).

¹H-NMR(CDCl₃) δ: 6.80-6.86(1H, m), 7.05-7.44(6H, m), 8.22(1H, dd),9.30(1H, brs)

Step 2

Preparation of N-(2-nitrophenyl)-N-(2-cyanoethyl)-2-fluoroaniline

N-(2-Nitrophenyl)-2-fluoroaniline (17.8 g) was dissolved inacrylonitrile (100 ml), triton B (40% benzyltrimethylammonium hydroxidein methanol) (1.0 ml) was added, the mixture was stirred at 50-60° C.for 3 hours. The reaction mixture was concentrated under reducedpressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1), to thereby obtain 6.37 g of the titledcompound as a orange color crystal.

¹H-NMR(CDCl₃) δ: 3.81(2H, brs), 5.36(1H, brs), 6.64-7.13(8H, m)

Step 3

Preparation of N-(2-aminophenyl)-N-(2-cyanoethyl)-2-fluoroaniline

N-(2-Nitrophenyl)-N-(2-cyanoethyl)-2-fluoroaniline (6.37 g) wasdissolved in methanol (60 ml), 10% palladium carbon (0.60 g) was added,the mixture was stirred for 3 hours under hydrogen atmosphere. Palladiumcarbon was removed by filtration, the filtrate was concentrated underreduced pressure, to thereby obtain 6.17 g of the titled compound(Yield: 100%).

¹H-NMR(CDCl₃) δ: 2.73(2H, t), 4.08(2H, t), 6.87-7.77(8H, m)

Step 4

Preparation of 3-[N-(2-aminophenyl)-N-(2-fluorophenyl)3aminopropionicacid

N-(2-Aminophenyl)-N-(2-cyanoethyl)-2-fluoroaniline (6.18 g) wasdissolved in ethanol (40 ml), aqueous potassium hydroxide (12.5 g)solution (80 ml) was added, the mixture was refluxed for 3 hours. Thereaction mixture was allowed to cool, adjusted to pH 3 with concentratedhydrochloric acid, and extracted with methylene chloride. The organiclayer was successively washed with water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure, to thereby obtain 5.6 g of the titled compound as brownamorphous (Yield: 86%).

¹H-NMR(CDCl₃) δ: 2.68(2H, t), 3.86(2H, t), 6.70-7.10(8H, m)

Step 5

Preparation of2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

3-[N-(2-Aminophenyl)-N-(2-fluorophenyl)]aminopropionic acid (5.6 g) wasdissolved in xylene (60 ml), the solution was refluxed for 3 hours whilewater was removed by use of a Dean-Stark condenser. The reaction mixturewas concentrated under reduced pressure, the residue was suspended indiisopropyl ether and collected by filtration, to thereby obtain 4.60 gof the titled compound as a pale brown crystal (Yield: 88%).

¹H-NMR(CDCl₃) δ: 2.70(2H, t), 4.04(2H, t), 6.87-7.12(8H, m), 8.00(1H,brs)

Step 6

Preparation of1-methoxymethyl-2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere, 60% sodium hydride (0.38 g) was suspended inN,N-dimethylformamide (5 ml), a solution of2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.89g) in N,N-dimethylformamide (15 ml) was added dropwise over 15 minutesunder ice-cooling, the mixture was stirred for one hour at sametemperature. Chloromethylmethyl ether (0.89 g) was added thereto, theresultant mixture was stirred at room temperature for 2 hours. Water wasadded to the reaction mixture, extracted with chloroform, the organiclayer was successively washed with water and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 5.26 g ofthe titled compound as colorless amorphous (Yield: 98.4%).

¹H-NMR(CDCl₃) δ: 2.67(2H, t), 3.44(3H, s), 3.96(2H, t), 5.19(2H, s),6.90-7.23(7H, m), 7.48(1H, dd)

Step 7

Preparation of1-methoxymethyl-2-oxo-3-hydroxyimino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere,1-methoxymethyl-2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(5.26 g) was dissolved in toluene (50 ml), the mixture was cooled onice, potassium tert-butoxide (9.8 g) was added thereto at internaltemperature 10° C., and stirred for 30 minutes under ice-cooling.tert-Butyl nitrite (5.0 g) was added thereto, the mixture was allowed toroom temperature, and stirred for one hour and 30 minutes. Saturatedbrine was added to the reaction mixture, extracted with ethyl acetate.The organic layer was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (silica gel NH-DM1020, produced by FujisiliciaCo. Ltd., chloroform:methanol=20:1), to thereby obtain 2.35 g of thetitled compound as pale brown amorphous.

¹H-NMR(CDCl₃) δ: 3.51 and 3.53(3H, each s), 4.58 and 4.75(2H, each s),5.27 and 5.29(2H, each s), 6.89-7.23(7H, m), 7.53(1H, m)

Step 8

Preparation of1-methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-Methoxymethyl-2-oxo-3-hydroxyimino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.35 g) was dissolved in tetrahydrofuran (25 ml), propyl isocyanate(1.52 g) and triethylamine (1.81 g) were added thereto, and the mixturewas refluxed for 3 hours. The reaction mixture was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography (silica gel NH-DM1020, produced by Fujisilicia Co. Ltd.,chloroform), to thereby obtain 2.52 g of the titled compound as brownamorphous (Yield: 85%).

¹H-NMR(CDCl₃) δ: 0.87-0.97(3H, m), 1.46-1.57(2H, m), 3.14-3.23(2H, m),3.53(3H, s), 4.71(2H, brs), 5.00-5.60(3H, m), 6.93-7.28(7H, m),7.53-7.56(1H, m)

Step 9

Preparation of1-methoxymethyl-2-oxo-3-amino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-Methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.52 g) was dissolved in methanol (30 ml), 10% palladium carbon (0.60g) was added thereto, the mixture was swung for 4 hours under hydrogenatmosphere (3.5-3.0 kg/cm²). Palladium carbon was removed by filtration,the filtrate was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 0.48 g of the titledcompound as yellow-brown amorphous.

¹H-NMR(CDCl₃) δ: 3.45(3H, s), 3.70-3.77(1H, m), 4.06-4.12(1H, m),4.23(2H, brs), 4.96(1H, d), 5.50(1H, d), 6.91-7.49(8H, m)

Step 10

Preparation of2-oxo-3-benzyloxycarbonylamino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-Methoxymethyl-2-oxo-3-amino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.94 g) was dissolved in 25% hydrobromic acid-acetic acid solution (18ml), the mixture was stirred for one hour. The reaction mixture wasconcentrated under reduced pressure, diethyl ether was add, the solid soprecipitated was collected by filtration to give pale brown crystals.This crystals were suspended in water (5 ml), 1N aqueous sodiumhydroxide (4.5 ml) and a solution of benzyl chloroformate (301 mg) intetrahydrofuran (7 ml) were added thereto, the resultant mixture wasstirred for one hour. Water was added to the reaction mixture, extractedwith methylene chloride, the organic layer was successively washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1), to thereby obtain 291 mg of the titled compound asamorphous.

¹H-NMR(CDCl₃) δ: 3.49-3.60(1H, m), 4.35-4.50(1H, m), 4.63-4.70(1H, m),5.08(2H, s), 5.89(1H, brd), 6.88-7.46(13H, m), 7.76(1H, s)

Referential Example 10

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexene-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(3.00 g) obtained from Referential Example 7 was suspended in methanol(30 ml), 90% 3-bromocyclohexene (6.08 g) and sodium bicarbonate (2.85 g)were added, and the mixture was stirred for 5 hours at room temperature.The reaction mixture was concentrated under reduced pressure, water (100ml) was added to the residue, extracted with chloroform. The organiclayer was dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=2:1), tothereby obtain 1.36 g of the titled compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 1.44-2.05(6H, m), 2.27(3H, s),3.19-3.33(1H, m), 3.66-4.05(1H, m), 4.40-4.52(1H, m), 5.48(1H, d),5.63-5.93(2H, m), 6.75(1H, d), 6.91-7.11(2H1 m), 7.33(1H, brs)

MS(EI)m/z: 371(M⁺)

Step 2

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(500 mg) was suspended in xylene (20 ml), nitrobenzene (831 mg) and 10%palladium carbon (250 mg) were added therto, and the mixture wasrefluxed for 2 hours. The reaction mixture was allowed to cool,filtrated, and the filtrate was concentrated under reduced pressure.Diisopropyl ether was added to the residue, crystals so precipitatedwere collected by filtration, to thereby obtain 413 mg of the titledcompound (Yield: 83%).

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.34(3H, s), 3.65(1H, dd), 4.22(1H, dd),4.57-4.64(1H, m), 5.58(1H, d), 6.69-6.72(2H, m), 6.83(1H, t),6.92-6.99(2H, m), 7.08-7.20(3H, m), 7.74(1H, s)

The production methods of the compound (1) of the present invention willhereinafter be described.

Example 89

Preparation of3-[3-[1-(2-thienylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(30.0 g) obtained from Referential Example 7 was dissolved in methylenechloride (300 ml), pivaloyl chloride (15.0 g) and pyridine (9.8 g) wereadded thereto, the mixture was refluxed for 2 hours and 30 minutes. Thereaction mixture was allowed to cool, Water was added, and extractedwith chloroform. The organic layer was successively washed withsaturated aqueous sodium bicarbonate, water, and saturated brine, driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, to thereby obtain the 21.5 g of titled compound as whitecrystals.

¹H-NMR(CDCl₃) δ: 0.97(9H, s), 1.40(9H, s), 2.39(3H, s), 3.87(1H, dd),4.35(1H, t), 4.43-4.50(1H, m), 5.40(1H, d), 6.95(1H, s), 7.06(1H, d),7.14(1H, d), 7.93(1H, s)

Step 2

Preparation of1-(2-thenoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) was dissolved in tetrahydrofuran (10 ml), 60% sodium hydride(0.16 g) was added thereto under argon atmosphere, and the mixture wasstirred for 30 minutes at room temperature. A solution of2-bromoacetylthiophene (0.99 g) in tetrahydrofuran (1 ml) was added tothe resultant mixture, stirred for 2 hours. The reaction mixture waspoured into ice-water, extracted with ethyl acetate, the organic layerwas washed succesively with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.01 g of the titledcompound (Yield: 76%).

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.39(9H, s), 2.37(3H, s), 3.88-3.95(1H,m), 4.20-4.28(1H, m), 4.43(1H, d), 4.53-4.57(1H, m), 5.48(1H, brd),5.62(1H, d), 7.10-7.22(4H, m), 7.74-7.87(2H, m)

Step 3

Preparation of1-(2-thenoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Thenoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was dissolved in 4N HCl-dioxane (10 ml), the solution wasstirred for one hour at 55° C. The reaction mixture was concentratedunder reduced pressure. The residue was neutralized with saturatedaqueous sodium bicarbonate, extracted with methylene chloride. Theorganic layer was successively washed with water and saturated brine,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure, to thereby obtain 0.74 g of the titled compoundas brown crystals (Yield: 92%).

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 2.37(3H, s), 3.64-3.78(2H, m),4.20-4.27(1H, m), 4.36(1H, d), 5.75(1H, d), 7.07-7.22(4H, m),7.74-7.89(2H, m)

Step 4

Preparation of1-[1-(2-thenoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (0.23 g) was dissolved in tetrahydrofuran (10 ml),and the solution was cooled on ice-water. Triphosgene (0.15 g) was addedthereto at internal temperature 7° C., triethylamine (0.53 g) was addeddropwise thereto over 10 minutes period, the mixture was allowed to cometo room temperature, and stirred for 10 minutes. Subsequently, asuspension of1-(2-thenoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.52 g) in tetrahydrofuran (10 ml ) was added, and the resultantmixture was stirred for one hour. Water was added to the reactionmixture, extracted with methylene chloride, the organic layer wassuccessively washed with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=1:1), to thereby obtain 0.70 g ofthe titled compound as white crystals (Yield: 88%).

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 1.35(3H, t), 2.38(3H, s), 3.88-3.95(1H,m), 4.29-4.40(3H, m), 4.48(1H, d), 4.79-4.89(1H, m), 5.65(1H, d),6.10-6.22(1H, m), 7.10-7.27 (6H, m), 7.55-7.91 (5H, m)

Step 5

Preparation of3-[3-[1-(2-Thenoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Thenoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(0.67 g) was suspended in a mixed solvent of ethanol (10 ml) andtetrahydrofuran (10 ml), aqueous lithiumhydroxide monohydrate (0.24 g)solution (10 ml) was added, and the mixture was stirred for 3 hours atroom temperature. The reaction mixture was concentrated under reducedpressure, weakly acidified with 1N hydrochloric acid, extracted withmethylene chloride. The organic layer was successively washed with waterand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, the residue was suspendedin a mixed solvent of methanol and ethyl acetate, crystals soprecipitated were collected by filtration, to thereby obtain 0.48 g ofthe titled compound as white crystals (Yield: 78%).

Melting point: 198-206° C.

¹H-NMR(DMSO-d₆) δ: 0.96(9H, s), 2.38(3H, s), 3.61-3.68 (1H, m),4.21-4.30(1H, m), 4.46-4.53(1H, m), 4.86 (1H, d), 5.61 (1H, d), 6.65((1H, brd), 7.20-7.52 (7H, m), 8.00-8.20 (3H, m), 9.00(1H, brs),12.83(1H, brs)

Example 90

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-benzyloxycarbonylamino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.0 g) obtained from Referential Example 8,bromomethyl-tert-butylketone(0.94 g), toluene (30 ml), 1N aqueous sodium hydroxide (15 ml) and tetran-butylammonium bromide (20 mg) were mixed, the mixture was stirred for20 hours. The reaction mixture was separated into aqueous layer andorganic layer, the aqueous layer was extracted with ethyl acetate, theextract was combined with the former organic layer. The combined organiclayer was successively washed with water and saturated brine, dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.12 g ofthe titled compound as colorless crystals (Yield: 45%).

¹H-NMR(CDCl₃) δ: 1.26(9H, s), 3.57-3.65(1H, m), 3.79(3H, s), 4.11-4.21(1H, m), 4.26(1H, d), 4.63-4.72(1H, m), 5.08(2H, s), 5.14(1H, d),5.85(1H,brd), 6.41-6.85(5H, m), 7.12-7.34(8H, m)

Step 2

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-tert-Butylcarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.11 g) was dissolved in methanol (20 ml), 10% palladium carbon (220mg) was added, and the mixture was stirred for 2 hours under hydrogenatmosphere. Palladium carbon was removed by filtration, the filtrate wasconcentrated under reduced pressure, to thereby obtain 0.82 g of thetitled compound as colorless amorphous(Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.28(9H, s), 3.52-3.60(1H, m), 3.74-3.80(1H, m),3.78(3H, s), 3.90-3.96(1H, m), 4.16(1H, d), 5.26(1H, d), 6.63-6.84(5H,m), 7.11-7.22(3H, m)

Step 3

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (373 mg) was dissolved in tetrahydrofuran (20 ml),the solution was cooled on ice-water. Triphosgene (252 mg) was added atinternal temperature 5° C., triethylamine (870 mg) was added dropwisethereto over 15 minutes period, the mixture was allowed to come to roomtemperature, and stirred for 10 minutes. Furthermore, a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(820 mg) in tetrahydrofuran (20 ml), the resultant mixture was stirredfor one hour at room temperature. Water was added to the reactionmixture, extracted with methylene chloride, the organic layer wassuccessively washed with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl amorphous(Yield: 95%).

¹H-NMR(CDCl₃) δ: 1.20(9H, s), 1.38(3H, t), 3.71-3.75(1H, m), 3.80(3H,s), 4.11-4.16(1H, m), 4.33 (2H, q), 4.44(1H, d), 4.91-4.95(1H, m),5.11(1H, d), 6.27(1H, br), 6.67-7.65(12H, m), 7.94(1H, brs)

Step 4

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

1-(1-tert-Butylcarbonylmethyl-2-oxo-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea(1.17 g) was dissolved in a mixed solvent of tetrahydrofuran (20 ml) andethanol (20 ml), aqueous lithium hydroxide monohydrate (428 mg) solution(10 ml) was added, and the mixture was stirred for 7 hours at roomtemperature. The reaction mixture was concentrated under reducedpressure, the residue was weakly acidified with 1N hydrochloric acid,extracted with chloroform. The organic layer was successively washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure, the residuewas suspended in ethyl acetate for trituration, collected by filtration,to thereby obtain 616 mg of the titled compound.

Melting point: 202-203° C.

¹H-NMR(DMSO-d₆) δ: 1.17(9H, s), 3.55-3.63(1H, m), 3.78(3H, s),3.92-3.99(1H, m), 4.54-4.64(1H, m), 4.79(1H, d), 5.12(1H, d),6.69-7.54(12H, m), 8.01-8.03(1H, m), 9.10(1H, brs), 12.81(1H, br)

Example 91

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Referential Example 7 and potassium carbonate(1.10 g) were suspended in a mixed solvent of methylene chloride (30 ml)and water (20 ml). A solution of benzyl chloroformate (1.35 g) inmethylene chloride (10 ml) was added thereto under ice-cooling, and themixture was stirred for 2 hours at same temperature and then stirredovernight at room temperature. The reaction mixture was separated intoorganic layer and aqueous layer, the organic layer was successivelywashed with aqueous 10% oxalic acid solution, water, and saturatedbrine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure, to thereby obtain the 2.61 g oftitled compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 2.34(3H, s), 4.02(1H, br), 4.28(1H, br),4.46-4.51(1H, m), 4.99-5.17(2H, br), 5.48(1H, d), 6.87(1H, s),7.05-7.35(7H, br), 7.65(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(23.1 g) was suspended in toluene (320 ml),2-bromo-2′-methylacetophenone (13.9 g), 1N aqueous sodium hydroxide (160ml) and tetra-n-butylammonium bromide (400 mg) were added thereto, themixture was stirred for 2 hours at room temperature. After reaction, thereaction mixture was separated, the organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, the residue was purified bysilica gel column chromatography(n-hexane:ethyl acetate=4:1), to therebyobtain 12.9 g of the titled compound.

¹H-NMR(CDCl₃) δ: 1.39(9H, s), 2.34(3H, s), 2.46-2.52(3H, br), 3.98(1H,br), 4.29(1H, br), 4.53-4.62(1H, m), 4.75(1H, d), 5.01-5.18(3H, br),5.52(1H, d), 7.00(1H, s), 7.12-7.43(10H, br), 7.65(1H, br)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(12.9 g) was suspended in 4N HCl-dioxane (100 ml), the suspension wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, the residue was neutralized with saturatedaqueous sodium bicarbonate, extracted with methylene chloride, driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure, to thereby obtain 9.78 g of the titled compound(Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.57(2H, br), 2.34(3H, s), 2.49(3H, s), 3.68-3.78(2H,m), 4.19(1H, br), 4.56(1H, d), 5.13-5.25(3H, br), 6.99(1H, s), 7.05(1H,d), 7.25-7.41 (9H, br), 7.64(1H, d)

Step 4

Preparation of1-[l-(2-toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (4.29 g) was dissolved in tetrahydrofuran (600ml), triphosgene (2.54 g) was added under ice-cooling, triethylamine(2.19 ml) was added thereto five times every 3 minutes after dividedinto five portions. A solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(9.78 g) in tetrahydrofuran (200 ml) was added, the mixture was stirredfor 30 minutes, subsequently, stirred overnight at room temperature. Thereaction mixture was poured into water (3 L), acidified with 1Nhydrochloric acid, extracted with methylene chloride. The organic layerwas washed with saturated aqueous sodium bicarbonate, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=2:1), to thereby obtain 13.3 gof the titled compound.

¹H-NMR(CDCl₃) δ: 1.34(3H, t), 2.35(3H, brs), 2.39-2.47(3H, br), 4.01(1H,br), 4.33(2H, q), 4.41(1H, br), 4.81-4.87(2H, br), 5.00-5.21(3H, br),6.18(1H, br), 7.01(1H, brs), 7.11-7.41(12H, m), 7.53(1H, d),7.59-7.66(2H, m), 7.87(1H, brs)

MS(FAB)m/z: 649 (MH⁺)

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(435 mg) was dissolved in methanol (20 ml), aqueous lithium hydroxidemonohydrate (141 mg) solution (10 ml) and tetrahydrofuran (10 ml) wereadded, the mixture was refluxed for 2 hours. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved in water(150 ml), washed with diethyl ether (100 ml), acidified with 1Nhydrochloric acid, and extracted with methylene chloride. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure, n-hexane was added to the residue fortrituration, and collected by filtration, to thereby obtain 301 mg ofthe titled compound (Yield: 72.5%).

Melting point: 144-147° C.

¹H-NMR(CDCl₃) δ: 2.36(3H, s), 2.47-2.51(3H, br), 4.22-4.44(3H, br),4.79-4.85(2H, m), 5.03-5.23(3H, m), 7.01(1H, s), 7.17-7.47(11H, m),7.57-7.60(2H, m), 7.72 (1H, s), 8.22 (1H, s), 8.35 (1H, dd), 10.60( (1H,br)

MS(FAB)m/z: 621 (MH⁺)

Example 92

Preparation of3-[3-[1-(thiophen-3-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(thiophen-3-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) obtained from Step 1 of Example 89 was dissolved intetrahydrofuran (10 ml), 60% sodium hydride (0.16 g) was added underargon atmosphere, the mixture was stirred for 30 minutes at roomtemperature. A solution of 3-bromoacetylthiophene (0.90 g) intetrahydrofuran (5 ml) was added,stirred for one hour. The reactionmixture was poured into ice-water, extracted with ethyl acetate, theorganic layer was successively washed with water and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 0.94 g ofthe titled compound (Yield: 71%).

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.40(9H, s), 2.36(3H, s), 3.91-3.96(1H,m), 4.20-4.29(1H, m), 4.42(1H, d), 4.50-4.60(1H, m), 5.48(1H, brd),5.59(1H, d), 7.05-7.14(3H, m), 7.39-7.65(2H, m), 8.21-8.23(1H, m)

Step 2

Preparation of1-(thiophen-3-yl)carbonylmethyl-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(Thiophen-3-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.94 g) was dissolved in 4N HCl-dioxane (10 ml), the solution wasstirred for one hour at 55-60° C. The react ion mixture was concentratedunder reduced pressure, the residue was neutralized with saturatedaqueous sodium bicarbonate, and extracted with methylene chloride. Theorganic layer was successively washed with water and saturated brine,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure, to thereby obtain 0.69 g of the titled compoundas a brown solid(Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.61(2H, brs), 2.36(3H, s), 3.71-3.78(2H,m), 4.23-4.37(2H, m), 5.72(1H, d), 7.01-7.14(3H, m), 7.40-7.66(2H, m),8.22-8.24(1H, m)

Step 3

Preparation of1-[1-(thiophen-3-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (0.33 g) was dissolved in tetrahydrofuran (20 ml)and cooled on ice. Triphosgene (0.22 g) was added at internaltemperature 5° C., triethylamine (0.76 g) was added dropwise theretoover 10 minutes period, the mixture was allowed to come to roomtemperature,stirred for 10 minutes. A solution of1-(thiophen-3-yl)carbonylmethyl-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.69 g) in tetrahydrofuran (10 ml) was added, the resultant mixture wasstirred for one hour. Water was added to the reaction mixture, extractedwith methylene chloride, the organic layer was successively washed withwater and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, the residue waspurified by silica gel column chromatography(n-hexane:ethylacetate=1:1), to thereby obtain 0.86 g of the titled compound as palebrown crystals (Yield: 75%).

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 2.37(3H, s), 3.89-3.97(1H, m),4.29-4.49(4H, m), 4.80-4.87(1H, m), 5.62(1H, d), 6.10(1H,brd),7.04-7.67(9H, m), 7.89-7.91(1H, m), 8.20-8.22(1H, m)

Step 4

Preparation of3-[3-[1-(thiophen-3-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(Thiophen-3-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(0.85 g) was suspended in tetrahydrofuran (20 ml). Aqueous lithiumhydroxide monohydrate (0.29 g) solution (10 ml) was added, and themixture was stirred for 4 hours at room temperature. The reactionmixture was concentrated under reduced pressure, weakly acidified with1N hydrochloric acid, and concentrated under reduced pressure. Theresidue was collected by filtration, the resultant solid wassuccessively washed with water and ethyl acetate, to thereby obtain 0.65g of the titled compound as colorless crystals (Yield: 82%).

Melting point: 215-216° C.

¹H-NMR(DMSO-d₆) δ: 0.96(9H, s), 2.37(3H, s), 3.62-3.69(1H, m),4.22-4.30(1H, m), 4.47-4.54(1H, m), 4.80(1H, d), 5.58(1H, d),6.64(1H,brd), 7.16-8.00(10H, m), 8.71-8.73( (1H, m) , 9.01( (1H, brs) ,12.84(1H, brs)

Example 93

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(1.00 g) obtained from Step 4 of Example 91 was dissolved in ethanol (20ml), 10% palladium carbon (200 mg) was added, and under hydrogenatmosphere the mixture was stirred for 2 hours and addtionally stirredfor one hour at 50° C. The reaction mixture was filtrated through a padof Celite, the filtrate was concentrated under reduced pressure, tothereby obtain 500 mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.33(3H, t), 1.70(1H, br), 2.27(3H, s), 2.42(3H, s),3.46( (1H, t), 3.93(1H, dd), 3.41(2H, q), 4.90-4.99(1H, m), 5.03(1H, d),5.20(1H, d), 6.45(1H, d), 6.84-6.96(3H, m), 7.18-7.26(3H, m), 7.37(1H,t), 7.43(1H, s), 7.54-7.67(3H, m), 7.91(1H, s)

Step 2

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) was suspended in 1,2-dichloroethane (10 ml),2,2-dimethylbutyryl chloride (144 mg) and pyridine (86 μl ) were added,and the mixture was refluxed for one hour and 30 minutes. Water (100 ml)and ethyl acetate (100 ml) were added to the reaction mixture,separated, the organic layer was washed with 1N hydrochloric acid, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 248 mg ofthe titled compound.

¹H-NMR(CDCl₃) δ: 0.88(3H, t), 0.93(3H, s), 0.97(3H, s), 1.29-1.37(1H,m), 1.34(3H, t), 1.61-1.70(1H, m), 2.39(3H, s), 2.51(3H, s), 3.94(1H,dd), 4.32(2H, q), 4.33-4.44(2H, m), 4.81-4.91(1H, m), 5.55(1H, d),6.30(1H, d), 7.03(1H, s), 7.05-7.29(5H, m), 7.39-7.43(2H, m),7.56-7.60(2H, m), 7.67(1H, t), 7.90(1H, t)

Step 3

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureidolbenzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(239 mg) was dissolved in methanol (20 ml), aqueous lithium hydroxidemonohydrate (82 mg) solution (10 ml) and tetrahydrofuran (10 ml) wasadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, 1N hydrochloric acid was added,and extracted with methylene chloride. The organic layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and isopropyl ether was added to the residue for trituration,and collected by filtration, to thereby obtain 130 mg of the titledcompound.

Melting point: 153-155° C.

¹H-NMR(DMSO-d₆) δ: 0.78(3H, t), 0.82(3H, s), 0.88(3H, s), 1.20-1.28(1H,m), 1.50-1.60(1H, m), 2.39(3H, s), 2.46(3H, s), 3.69(1H, dd), 4.24(1H,t), 4.47-4.55(1H, m), 4.89(1H, d), 5.42(1H, d), 6.72(1H, d), 7.17(1H,s), 7.23(1H, d), 7.30-7.40(4H, m), 7.47-7.53(3H, m), 7.97-8.00(2H, m),9.01(1H, s), 12.80(1H, br) MS(FAB)m/z: 585(MH⁺)

Example 94

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3-chloro-2,2-dimethylpropionyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(3-chloro-2,2-dimethylpropionyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) obtained from Step 1 of Example 93 was suspended in1,2-dichloroethane (10 ml), chloropivaloyl chloride (166 mg) andpyridine (86 μl) were added, and the mixture was refluxed for 2 hours 30minutes. The reaction mixture was successively washed with water,1Nhydrochloric acid, and saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 509 mg ofthe titled compound (Yield: 81%).

¹H-NMR(CDCl₃) δ: 0.96(3H, s), 1.16(3H, s), 1.35(3H, t), 2.39(3H, s),2.52(3H, s), 3.42(1H, d), 3.70(1H, d), 3.98(1H, dd), 4.33(2H, q),4.39(1H, t), 4.50(1H, d), 4.83-4.93(1H, m), 5.56(1H, d), 6.21(1H, d),7.06(1H, s), 7.12-7.14(2H, m), 7.21-7.30(4H, m), 7.43(1H, t), 7.54(1H,dd), 7.64(1H,dt), 7.74(1H, d), 7.90(1H, t)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3-chloro-2,2-dimethylpropionyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

-[1-(2-Toluoylmethyl)-2-oxo-5-(3-chloro-2,2-dimethylpropionyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(491 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxidemonohydrate (159 mg) solution (12 ml) was added, the mixture wasrefluxed for 30 minutes. The reaction mixture was concentrated underreduced pressure,1N hydrochloric acid was added, and extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure, diisopropyl ether was added to the residue fortrituration, collected by filtration,to thereby obtain 320 mg of thetitled compound.

Melting point: 224-226° C.

¹H-NMR(DMSO-d₆) δ: 0.86(3H, s), 1.06(3H, s), 2.40(3H, s), 2.45(3H, s),3.52(1H, d), 3.70-3.75(2H, m), 4.24(1H, t), 4.49-4.59(1H, m), 4.92(1H,d), 5.41(1H, d), 6.73(1H, d), 7.21(1H, s), 7.27(1H, t), 7.33-7.42(4H,m), 7.47-7.53(3H, m), 7.96(1H, d), 8.01(1H, s), 9.02(1H, s), 12.84(1H,s) MS(FAB)m/z: 605(MH⁺)

Example 95

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

60% Sodium hydride (33 mg) was suspended in anhydrousN,N-dimethylformamide (10 ml), under ice-cooling2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(200 mg) obtained from Referentioal Example 5, and the mixture wasstirred for one hour at room temperature. Subsequently,bromomethyl-tert-butylketone (147 mg) was added, stirred for one hour atroom temperature. Ice-water was added to the reaction mixture, extractedwith ethyl acetate, the organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, diisopropyl ether was added to the residue forcrystallization, crystals so precipitated were collected by filtration,to thereby obtain 140 mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.27(9H, s), 1.42(9H, s), 2.32(3H, s), 3.58(1H, dd),4.17(1H, dd), 4.25(1H, d), 4.55-4.65(1H, m), 5.13(1H, d), 5.62(1H, d),6.73-6.91(4H, m), 6.97-7.22(4H, m)

Step 2

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

4N HCl-dioxane (5 ml) was added to a solution of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(100 mg) in ethanol (5 ml ), the mixture was stirred at 50° C. for 30minutes. The reaction mixture was concentrated under reduced pressure,the residue was neutralized with saturated aqueous sodium bicarbonate,extracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, the solvent was evaporated under reduced pressure, tothereby obtain 78 mg of the titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.29(9H, s), 1.66 (2H, brs), 2.33 (3H, s), 3.55 (1H,dd), 3.75 (1H, dd), 3.94(1H, dd), 4.16(1H, d), 5.24(1H, d), 6.71-6.91(4H, m), 6.95-7.03(1H, m), 7.09 (1H, d), 7.14-7.24 (2H, m)

Step 3

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (14 mg) was dissolved in anhydrous tetrahydrofuran(10 ml), under ice-cooling triphosgene (68 mg) was added andtriethylamine (60 μl ) was added thereto five times. The mixture wasstirred for 30 minutes at same temperature. A solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(227 mg) in anhydrous tetrahydrofuran (10 ml) was added, the resultantmixture was allowed to come to room temperature, and stirred for 30minutes. The reaction mixture was concentrated under reduced pressure,Water (50 ml) was added, and extracted with methylene chloride. Theorganic layer was dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, and diethyl ether was added to theresidue for trituration, collected by filtration, to thereby obtain 280mg of the titled compound (Yield: 81.1%).

¹H-NMR(CDCl₃) δ: 1.23(9H, s), 1.35(3H, t), 2.34(3H, s), 3.76(1H, dd),4.13(1H, dd), 4.33(2H, q), 4.48 (1H, d), 4.93(1H, ddd), 5.07(1H, d),6.38(1H, d), 6.72-6.83(3H, m), 6.93-7.28(8H, m), 7.32-7.39(1H, m),7.61(1H, dt), 7.96(1H, t)

Step 4

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid1-(1-tert-Butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea(280 mg) was dissolved in a mixed solvent of methanol (20 ml) andtetrahydrofuran (10 ml), aqueous lithium hydroxide monohydrate (106 mg)solution (10 ml) was added, and the mixture was refluxed for one hour.The reaction mixture was concentrated under reduced pressure, adjustedto pH 1-2 with 1N hydrochloric acid, and extracted with methylenechloride. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, diisopropyl ether was added to the residue for trituration andcollected by filtration, to thereby obtain 200 mg of the titledcompound.

Melting point: 240-243° C.(decomposition)

¹H-NMR(CDCl₃) δ: 1.30(9H, s), 2.35(3H, s), 3.70(1H, dd), 4.27(1H, d),4.38(1H, dd), 4.85(1H, ddd), 5.21(1H, d), 6.79(2H, d), 6.86(1H, t),6.96(1H, brs), 7.05(1H, dd), 7.12-7.27(4H, m), 7.38(1H, t), 7.52(1H, d),7.61(1H, d), 7.72-7.78(1H, m), 8.30(1H, brs), 8.40(1H, dd),10.70-10.90(1H, br)

MS(FAB)m/z: 529(MH⁺)

Example 96

Preparation of(+)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureidozbenzoicacid

Step 1

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-tert-butoxycarbonylamino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere,1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(4.75 g) obtained from Step 2 of Example 95 was dissolved in anhydrousN,N-dimethylformamide (40 ml), N-tert-butoxycarbonyl-L-phenylalanine(3.80 g), 1-hydroxybenzotriazole (1.93 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.74 g) andtriethylamine (3.65 ml) were added under ice-cooling, the mixture wasstirred for 5 minutes at same temperature, and subsequently theresultant mixture was allowed to come to room temperature, stirred for 2hours. Ice-water was added to the reaction mixture, extracted with ethylacetate, the organic layer was washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 8.06 g ofthe titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.25 and 1.26(9H, each s), 1.41(9H, s), 2.32 and2.34(3H, each s), 3.00-3.08(2H, m), 3.16 and 3.45(1H, each dd),3.96-4.45(4H, m), 4.77(1H, ddd), 4.95-5.04(1H, br), 5.08(1H, d),6.70(2H,dt), 6.80-6.94(2H, m), 6.97-7.05(1H, m), 7.06-7.12(1H, m),7.14-7.38(7H, m)

Step 2

Preparation of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineand(−)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-tert-Butylcarbonylmethyl-2-oxo-3-[(2S)-(2-tert-butoxycarbonylamino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(8.06 g) was dissolved in 4N HCl-dioxane (40 ml), the solution wasstirred for one hour at room temperature. The reaction mixture wasconcentrated under reduced pressure, neutralized with saturated aqueoussodium bicarbonate, and extracted with methylene chloride. The organiclayer was dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography(ethyl acetate contained water), to therebyobtain 3.01 g of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineof first eluent and 3.17 g of(−)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineof second eluent.

Data of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

[α]D²⁷(C=1.007, CHCl₃): +31.5°

¹H-NMR(CDCl₃) δ: 1.26(9H, s), 1.53(2H, brs), 2.34(3H, s), 2.77(1H, dd),3.20(1H, dd), 3.47(1H, dd), 3.62(1H, dd), 4.07-4.18(1H, m), 4.28(1H, d),4.85(1H,dt), 5.11(1H, d), 6.74(2H,dq), 6.85(1H, tt), 6.91 (1H, q),7.01(1H, dd), 7.11(1H, d), 7.15-7.38(7H, m), 8.13(1H, d)

Data of(−)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

[α]D²⁵(C=1.027, CHCl₃): −111.7°

¹H-NMR(CDCl₃) δ: 1.27(9H, s), 1.53(2H, brs), 2.33(3H, s), 2.67(1H, dd),3.21 (1H, dd), 3.42(1H, dd), 3.58 (1H, dd), 4.07-4.18(1H, m), 4.29(1H,d), 4.83(1H,dt), 5.11(1H, d), 6.73(2H,dq), 6.84(1H, tt), 6.91 (1H, q),7.01(1H, dd), 7.08-7.37(8H, m), 7.86(1H, d)

Step 3

Preparation of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-[2-(N-phenylthioureido)-3-phenylpropionyl]amino]-5-phenyl-8-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

(+)-1-tert-Butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.94 g) was dissolved in anhydrous methylene chloride (30 ml), phenylisothiocyanate (1.55 g) was added, and the mixture was stirred at roomtemperature for 2 hours and 30 minutes. The reaction mixture wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain3.50 g of the titled compound (Yield: 94.3%).

[α]D²⁵(C=1.001, CHCl₃): +71.7°

¹H-NMR(CDCl₃) δ: 1.28(9H, s), 2.33(3H, s), 3.17(2H, d), 3.52(1H, dd),4.07-4.19(1H, m), 4.20(1H, d), 4.75(1H,dt), 5.14(1H, d), 5.20(1H, q),6.66-6.77(4H, m), 6.84(1H,tt), 6.90(1H, q), 6.95-7.38(13H, m), 7.74(1H,s)

Step 4

Preparation of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

(+)-1-tert-Butylcarbonylmethyl-2-oxo-3-[(2S)-[2-(N-phenylthioureido)-3-phenylpropionyl]amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(3.24 g) was dissolved in trifluoroacetic acid (40 ml), the solution wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, neutralized with saturated aqueous sodiumbicarbonate, and extracted with methylene chloride. The organic layerwas dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography(chloroform:methanol=20:1), to thereby obtain 1.44g of the titled compound.

Optical purity: 99%ee (the ee value was determined by High PerformanceLiquid Chromatography)

[α]D²⁷(C=1.04, CHCl₃): +22.1°

Step 5

Preparation of(+)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea

Diphenylphosphoryl azide (1.38 g) and triethylamine (0.77 ml) were addedto a solution of isophthalic acid benzyl ester (1.15 g) in anhydrousdioxane (20 ml), the mixture was stirred at 60° C. for 30 minutes andsubsequently stirred at internal temperature 80° C. for one hour. Thereaction mixture was allowed to come to room temperature, a solution of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.1 g) in anhydrous dioxane (20 ml) was added thereto, the mixture wasstirred for 2 hours at room temperature. The resultant mixture wasconcentrated under reduced pressure, chloroform was added, the mixturewas washed succesively with saturated aqueous sodium bicarbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, the residue was purified bysilica gel column chromatography(n-hexane:ethyl acetate=2:1), to therebyobtain 622 mg of the titled compound.

[α]D²⁷ (C=1.028, CHCl₃): +47.2°

¹H-NMR(CDCl₃) δ: 1.23(9H, s), 2.34(3H, s), 3.72(1H, dd), 4.10(1H, dd),4.40(1H, d), 4.95(1H, dt), 5.15(1H, d), 5.31(1H, d), 5.32(1H, d),6.57(1H, d), 6.75(2H, d), 6.83(1H, t), 6.93(1H, brs), 7.0 1(1H,d d),7.06-7.52(11H, m), 7.60(1H, dt), 8.02(1H, t)

Step 6

Preparation of(+)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)]ureido]benzoicacid

Ethanol (20 ml) and 10% palladium carbon (100 mg) were added to(+)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea(840 mg), under hydrogen atmosphere the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was filtrated, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography(chloroform:methanol=10:1),a mixed solvent of ethyl acetate and diisopropyl ether was added to thecompound so precipitated for trituration, collected by filtration, tothereby obtain 360 mg of the titled compound.

Optical purity: 99%ee (the ee value was determined by High PerformanceLiquid Chromatography)

[α]D²⁷(C=1.005, MeOH): +108.1°

Example 97

Preparation of(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)]ureidolbenzoicacid

Step 1

Preparation of(−)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-[2-(N-phenylthioureido)-3-phenylpropionyl]amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 3 of Example 96 was repeated except that(−)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.2 g) obtained from Step 2 of Example 96 was used instead of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.94 g), to thereby obtain 2.68 g of the titled compound(Yield: 96.2%).

[α]D²⁶(C=1.043, CHCl₃): −19.3°

¹H-NMR(CDCl₃) δ: 1.24(9H, s), 2.30(3H, s), 2.94(1H, dd), 3.10(1H, dd),3.43(1H, dd), 3.91(1H, dd), 4.20(1H, d), 4.71(1H, dt), 5.06(1H, d),5.12-5.22(1H, m), 6.38(1H, d), 6.66(2H,dq), 6.75(1H, d), 6.85(2H, tt),6.95-7.43(12H, m), 7.71(1H, s)

Step 2

Preparation of(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

(−)-1-tert-Butylcarbonylmethyl-2-oxo-3-[(2S)-[2-(N-phenylthioureido)-3-phenylpropionyl]amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.50 g) was dissolved in trifluoroacetic acid (30 ml), the solution wasstirred at 50° C. for one hour. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in methanol (50 ml),concentrated hydrochloric acid (20 ml) was added, and refluxed for onehour. The resultant mixture was concentrated under reduced pressure,neutralized with saturated aqueous sodium bicarbonate, and extractedwith methylene chloride. The organic layer was dried over anhydroussodium sulfate, the solvent was evaporated under reduced pressure, andthe residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=20:1), to thereby obtain 1.40 gof the titled compound.

Optical purity: 99%ee (the ee value was determined by High PerformanceLiquid Chromatography)

[α]D²⁷(C=1.03, CHCl₃): −21.4°

Step 3

Preparation of(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea

Step 5 of Example 96 was repeated except that(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of(+)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the titled compound.

[α]D²⁷(C=1.035, CHCl₃): −48.0°

Step 4

Preparation of(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 6 of Example 96 was repeated except that(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)ureawas used instead of(+)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea,to thereby obtain the titled compound.

Optical purity: 99%ee (the ee value was determined by High PerformanceLiquid Chromatography)

[α]D²⁷(C=1.04, MeOH ): −111.3°

Example 98

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-isobutyryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-isobutyryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) obtained from Step 1 of Example 93 was suspended in1,2-dichloroethane (10 ml), isobutyryl chloride (114 mg) and pyridine(86 μl) were added thereto at room temperature, and the mixture wasrefluxed for 2 hours and 30 minutes. The reaction mixture was allowed tocool, washed with saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 647 mg ofthe titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: H, tt), 3.86(1H, d d), 4.33(2H, q), 4.61(1H, t),4.78(1H, d), 4.86-4.96(1H, m), 5.31(1H, d), 6.36(1H, d), 7.06(1H, s),7.11-7.31(5H, m), 7.38(1H, t), 7.63-7.70(3H, m), 7.79(1H, br s),7.91(1H, t)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-isobutyryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid1-[1-(2-Toluoylmethyl)-2-oxo-5-isobutyryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(560 mg) was dissolved in methanol (28 ml), aqueous lithium hydroxidemonohydrate (201 mg) solution (14 ml) and tetrahydrofuran (14 ml) wereadded, the mixture was refluxed for one hours. The reaction mixture wasconcentrated under reduced pressure, 1N hydrochloric acid was added, andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and diisopropyl ether was added to the residue for trituration,collected by filtration, to thereby obtain 360 mg of the titled compound(Yield: 67.4%).

Melting point: 162-165° C.

¹H-NMR(DMSO-d₆) δ: 0.93(3H, d), 1.04(3H, d), 2.32-2.41(1H, m), 2.39(3H,s), 2.41(3H, s), 3.60(1H, dd), 4.43(1H, t), 4.52-4.62(1H, m), 5.11(1H,d), 5.36(1H, d), 6.75(1H, d), 7.24-7.42(6H, m), 7.46-7.53(3H, m),7.96(1H, d), 8.01(1H, t), 9.06(1H, s), 12.82(1H, brs)

MS (FAB) m/z: 579 (M⁺+Na)

Example 99

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-propylpentanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yllureidolbenzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2-propylpentanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(³-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(⁵⁰⁰mg) obtained from Step 1 of Example 93 was suspended in1,2-dichloroethane (10 ml), 2-n-propylpentanoyl chloride (174 mg) andpyridine (87 μl) were added, the mixture was refluxed for 2 hours. Thereaction mixture was allowed to cool, successively washed with 1Nhydrochloric acid and saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 625 mg ofthe titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 0.69(3H, t), 0.89(3H, t), 0.92-1.68(8H, m), 1.35(3H,t), 2.25-2.38(1H, m), 2.38(3H, s), 2.54(3H, s), 3.88(1H, dd), 4.32(2H,q), 4.33(1H, d), 4.90-5.00(1H, m), 5.60(1H, d), 6.37(1H, br), 7.00(1H,s), 7.13-7.30(5H, m), 7.42(1H, t), 7.58-7.69(4H, m), 7.95(1H, s)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-propylpentanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yllureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-propylpentanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(540 mg) was dissolved in methanol (28 ml). Aqueous lithium hydroxidemonohydrate (177 mg) solution (14 ml) and tetrahydrofuran (14 ml) wereadded, the mixture was refluxed for 45 minutes. The reaction mixture wasconcentrated under reduced pressure, 1N hydrochloric acid was added tothe residue, extracted with methylene chloride. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure, and diisopropyl ether wasadded to the residue for trituration, collected by filtration, tothereby obtain 408 mg of the titled compound (Yield: 79.3%).

Melting point: 232-234° C.

¹H-NMR(DMSO-d₆) δ: 0.70(3H, t), 0.82(3H, t), 0.92-1.60(8H, m), 2.14-2.19(1H, m), 2.39 (3H, s), 2.46(3H, s), 3.60-3.67(1H, m), 4.43(1H, t),4.56-4.66(1H, m), 4.88(1H, d), 5.35(1H, d), 6.73(1H, d), 7.16(1H, s),7.25-7.41(5H, m) 7.467-7.54(3H, m), 7.92(1H, d), 8.01(1H, t), 9.04(1H,s), 12.84(1H, brs)

MS (FAB)m/z: 613 (MH⁺)

Example 100

Preparation of2-fluoro-5-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(4.00 g) obtained from Step 1 of Example 89 was suspended in toluene (56ml), 2-bromo-2′-methylacetophenone (2.72 g), 1N aqueous sodium hydroxide(28 ml) and tetra n-butylammonium bromide (40 mg) were added, and themixture was stirred overnight at room temperature. The reaction mixturewas weakly acidified with 1N hydrochloric acid, extracted with methylenechloride. The organic layer was washed with saturated aqueous sodiumbicarbonate, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. Diisopropyl ether was added to theresidue for trituration, collected by filtration, to thereby obtain 4.54g of the titled compound.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.40(9H, s), 2.37(3H, s), 2.57(3H, s),3.93(1H, dd), 4.26(1H, t), 4.45(1H, d), 4.53-4.59(1H, m), 5.49(1H, d),5.51 (1H, d), 7.04-7.15 (3H, m), 7.28-7.34(2H, m), 7.42-7.48(1H, m),7.75-7.78(1H, m)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension wasstirred at 50° C. for one hour. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in water, the solutionwas washed with diethyl ether, alkaline with saturated aqueous sodiumbicarbonate, and extracted with methylene chloride. The organic layerwas dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography (ethyl acetate), to thereby obtain 538 mg of the titledcompound.

¹H-NMR(CDCl₃) δ: 1.02(9H, s), 1.66(2H, br), 2.38(3H, s), 2.59(3H, s),3.66-3.78(2H, m), 4.19-4.28(1H, m), 4.36(1H, d), 5.65(1H, d), 7.01(1H,s), 7.07-7.12(2H, m), 7.29-7.49(3H, m), 7.81(1H, m)

Step 3

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-fluorophenyl)urea

Methyl 5-amino-2-fluorobenzoate (241 mg) was dissolved intetrahydrofuran (43 ml), under ice-cooling triphosgene (142 mg) wasadded and triethylamine (123 μl) were added five times every 3 minutes,a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(528 mg) in tetrahydrofuran (20 ml) was added thereto, and the mixturewas allowed to come to room temperature and stirred at room temperaturefor 2 hours. The reaction mixture was concentrated under reducedpressure, water (50 ml) was added, and extracted with methylenechloride. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 543 mg ofthe titled compound (Yield: 69.3%).

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 2.39(3H, s), 2.47(3H, s), 3.84(3H, s),3.84-3.39(1H, m), 4.39(1H, t), 4.45(1H, d), 4.84-4.92(1H, m), 5.55(1H,d), 6.57(1H, d), 6.91(1H, dd), 7.02(1H, s), 7.11-7.29(4H, m),7.38-7.45(3H, m), 7.68(1H, d), 7.86(1H, dd)

Step 4

Preparation of2-fluoro-5-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-fluorophenyl)urea(510 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxidemonohydrate (178 mg) solution (12 ml) and tetrahydrofuran (12 ml) wasadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, 1N hydrochloric acid was added,and extracted with methylene chloride. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure, and diisopropyl ether was added tothe residue for trituration, collected by filtration, to thereby obtain320 mg of the titled compound.

Melting point: 225-228° C.

¹H-NMR(CDCl₃) δ: 1.07(9H, s), 2.39(3H, s), 2.55(3H, s), 4.10(1H, dd),4.40(1H, t), 4.57(1H, d), 4.75-4.81(1H, m), 5.50(1H, d), 7.04-7.35(7H,m), 7.48(1H, t), 7.56(1H, dd), 7.71(1H, d), 8.05(1H, s), 8.31-8.34(1H,m), 11.00(1H, br) MS(FAB)m/z: 589(MH⁺)

Example 101

Preparation of3-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-benzyloxycarbonylamino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(291 mg) obtained from Referential Example9,bromomethyl-tert-butylketone (171 mg), toluene (5 ml), 1N aqueoussodium hydroxide (5 ml) and tetra n-butylammonium bromide (28 mg) weremixed, the mixture was stirred for 20 hours. The reaction mixture wasseparated into aqueous layer and organic layer, the aqueous layer wasextracted with ethyl acetate, the extract was combined with the formerorganic layer. The combined organic layer was successively washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography(n-hexane:ethylacetate=3:1), to thereby obtain 205 mg of the titled compound ascolorless amorphous.

¹H-NMR(CDCl₃) δ: 1.28(9H, s), 3.43-3.51(1H, m), 4.11(1H, d),4.39-4.45(1H, m), 4.68-4.72(1H, m), 5.07(2H, s), 5.33(1H, d), 5.88(1H,brd), 6.87-7.34(13H, m)

Step 2

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-tert-Butylcarbonylmethyl-2-oxo-3-benzyloxycarbonylamino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(205 mg) was dissolved in methanol (10 ml), 10% palladium carbon (30 mg)was added, under hydrogen atmosphere the filtration, the filtrate wasconcentrated under reduced pressure, to thereby obtain 150 mg of thetitled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.19(9H, s), 3.48(2H, s), 4.01-4.09(1H, m), 4.26(1H,d), 4.30-4.39(1H, m), 4.61-4.65(1H, m), 5.20(1H, d), 6.84-7.23(8H, m)

Step 3

Preparation of1-[1-tert-butylcarbonylmethyl-2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (69 mg) was dissolved in tetrahydrofuran (10 ml),the solution was cooled on ice-water. Triphosgene (45 mg) was added atinternal temperature 5° C., triethylamine (162 mg) was added theretoover 10 minutes period, the mixture was allowed to come to roomtemperature and stirred for 10 minutes. A solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(150 mg) in tetrahydrofuran (5 ml), the mixture was additionallychloride. The organic layer was successively washed with water andsaturated brine, dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography(n-hexane:ethyl acetate=3:1), to therebyobtain 190 mg of the title compound as colorless crystals (Yield: 83%).

¹H-NMR(CDCl₃) δ: 1.27(9H, s), 1.37(3H, t), 3.50-3.57(1H, m), 4.20(1H,d), 4.35(2H, q), 4.39-4.49(1H, m), 4.90-4.94(1H, m), 5.31(1H, d),6.05(1H, brd), 6.64(1H, brs), 6.87-7.93(12H, m)

Step 4

Preparation of3-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureidolbenzoicacid

1-[1-tert-butylcarbonylmethyl-2-oxo-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(190 mg) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) andethanol (10 ml), aqueous lithium hydroxide monohydrate (210 mg) solution(10 ml) was added, and the mixture was stirred at room temperature for 7hours. The reaction mixture was concentrated under reduced pressure,weakly acidified with 1N hydrochloric acid, and extracted withchloroform. The organic layer was successively washed with water andsaturated brine, the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel columnchromatography(chloroform:methanol=10:1), to thereby obtain 140 mg ofthe titled compound (Yield: 78%).

Melting point: 226-227° C.

¹H-NMR(CDCl₃) δ: 1.31(9H, s), 1.56(3H, brs), 3.49-3.62(1H, m), 4.14(1H,d), 4.57-4.63(1H, m), 4.87-4.91 (1H, m), 5.41 (1H, d), 6.79-7.74(10H,m), 8.29-8.41 (2H, m)

Example 102

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-ethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2-ethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) obtained from Step 1 of Example 93 was suspended in1,2-dichloroethane (10 ml), 2-ethyl-n-butanoyl chloride (144 mg) andpyridine (87 μl) were added thereto, the mixture was refluxed for 2hours. Water (100 ml) and ethyl acetate (100 ml) were added to thereaction mixture, and separated. The organic layer was washed with 1Nhydrochloric acid, dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography(n-hexane:ethyl acetate=2:1), to therebyobtain 666 mg of the titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 0.71(3H, t), 0.93(3H, t), 1.29-1.38(1H, m), 1.35(3H,t), 1.41-1.57(2H, m), 1.63-1.76(1H, m), 2.10-2.20(1H, m), 2.39(3H, s),2.52(3H, s), 3.90(1H, dd), 4.31(2H, d), 4.33(2H, q), 4.66(1H, t),4.89-4.96 (1H, m), 5.55 (1H, d), 6.34 (1H, d), 7.03 (1H, s), 7.15-7.30(5H, m), 7.40 (1H, t), 7.58-7.68(4H, m), 7.91(1H, t)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-ethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-ethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(510 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxidemonohydrate (175 mg) solution (12 ml) and tetrahydrofuran (12 ml) wereadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, 1N hydrochloric acid was addedto the residue, and extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure, isopropyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 339 mg of thetitled compound.

Melting point: 244-246° C.

¹H-NMR(DMSO-d₆) δ: 0.64(3H, t), 0.82(3H, t), 1.23-1.42(3H, m),1.56-1.67(1H, m), 1.95-2.03(1H, m), 2.40(3H, s), 2.46(3H, s), 3.65(1H,dd), 4.44(1H, t), 4.56-4.66(1H, m), 4.91 (1H, d), 5.33 (1H, d), 6.74(1H, d), 7.15 (1H, s) ,7.25-7.40(5H, m), 7.47-7.53(3H, m), 7.92(1H, d),8.01(1H, t), 9.02(1H, s), 12.82(1H, brs)

MS(FAB)m/z: 585(MH⁺)

Example 103

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-methylpentanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2-methylpentanoyl)-8methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) obtained from Step 1of Example 93 was suspended in1,2-dichloroethane (10 ml), 2-methyl-n-pentanoyl chloride (144 mg) andpyridine (87 μl) were added, the mixture was refluxed for 3 hours. Water(100 ml) and ethyl acetate (100 ml) were added to the reaction mixture,separated, the organic layer was washed with 1N hydrochloric acid, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 569 mg ofthe titled compound (Yield: 95.7%).

¹H-NMR(CDCl₃) δ: 0.70 and 0.87(3H, respectively t), 0.97 and 1.16(3H,respectively d), 1.16-1.80(4H, m), 1.35(3H, t), 2.29-2.45(1H, m),2.38(3H, s), 2.48-2.53(3H, s), 3.8-3.90(1H, m), 4.33(2H, q),4.41-4.70(2H, m), 4.87-4.97(1H, m), 5.48(1H, t), 6.30(1H, d), 7.04(1H,s), 7.15-7.31(5H, m), 7.36-7.41(1H, m), 7.55(1H, s), 7.63-7.69(3H, m),7.92(1H, s)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-methylpentanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-methylpentanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(560 mg) was dissolved in methanol (26 ml), aqueous lithium hydroxidemonohydrate (192 mg) solution (13 ml) and tetrahydrofuran (13 ml) wereadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, 1N hydrochloric acid was added,and extracted with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and diisopropyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 319 mg of thetitled compound.

Melting point: 227-229° C.

¹H-NMR(DMSO-d₆) δ: 0.69 and 0.81(3H, respectively t), 0.87 and 1.02(3H,respectively d), 0.81-1.63(4H, m), 2.18-2.29(1H, m), 2.39(3H, s), 2.43and 2.45(3H, s), 3.58-3.66(1H, m), 4.35-4.62(2H, m), 4.99(1H, dd),5.36(1H, dd), 6.73(1H, d), 7.20-7.41(6H, m), 7.47-7.53(3H, m), 7.95(1H,t), 8.01(1H, t), 9.03(1H, s), 12.83(1H, brs)

MS(FAB)m/z: 585(MH)⁺

Example 104

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) obtained from Step 1 of Example 93 was suspended in1,2-dichloroethane (10 ml), 2-thienylcarbonyl chloride (157 mg) andpyridine (87 μl) were added, and the mixture was refluxed for 2 hours.Water (100 ml) and ethyl acetate (100 ml) were added, separated, theorganic layer was washed with 1N hydrochloric acid, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was washed with diethyl ether, to thereby obtain553 mg of the titled compound (Yield: 91.3%).

¹H-NMR(CDCl₃) δ: 1.34(3H, t), 2.39(3H, s), 2.42(3H, s), 4.12(1H, dd),4.32(2H, q), 4.65(1H, t), 4.78(1H, d), 5.00-5.10(1H, m), 5.39(1H, d),6.41(1H, d), 6.83(1H, dd), 7.02-7.09(3H, m), 7.13(1H, s), 7.20-7.41(6H,m), 7.52(1H, ddd), 7.63(1H, dt), 7.71(1H, d), 7.91(1H, t)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(495 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxidemonohydrate (166 mg) solution (12 ml) and tetrahydrofuran (12 ml) wereadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, 1N hydrochloric acid was addedto the residue, and extracted with ethyl acetate. The organic layer wasdried over anhydrous magnesium sulfate, the solvent was evaporated underreduced pressure, and diisopropyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 289 mg of thetitled compound.

Melting point: 219-222° C.

¹H-NMR(DMSO-d₆) δ: 2.35(3H, s), 2.39(3H, s), 3.89(1H, dd), 4.36(1H, t),4.63-4.73(1H, m), 5.15(1H, d), 5.40(1H, d), 6.73(1H, brs), 6.81-6.89(2H,m), 7.10-7.19(2H, m), 7.31-7.37(4H, m), 7.45-7.55(3H, m), 7.65(1H, dd),7.94(1H, d), 8.03(1H, s), 9.06(1H, s), 12.84(1H, brs)

MS(FAB)m/z: 597(MH⁺)

Example 105

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Referential Example 7 was suspended in1,2-dichloroethane (40 ml), picolinoyl chloride hydrochloride (1.41 g)and pyridine (1.28 ml) were added, and the mixture was refluxed for 1hour and 30 minutes. The reaction mixture was concentrated under reducedpressure, the residue was dissolved in ethyl acetate (150 ml),successively washed with water and saturated aqueous sodium bicarbonate,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, diethyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 1.75 g of thetitled compound.

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.25(3H, s), 4.15(1H, dd), 4.50(1H, t),4.64-4.71(1H, m), 5.59(1H, d), 6.61-6.69(2H, m), 6.89(1H, s), 7.12(1H,dd), 7.38(1H, d), 7.56(1H, dt), 8.26-8.28(2H, m)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.74 g) was suspended in toluene (24 ml), 2-bromo-2′-methylacetophenone(1.12 g), 1N aqueous sodium hydroxide (12 ml) and tetra n-butylammoniumbromide (20 mg) were added, the mixture was stirred for one day at roomtemperature. The reaction mixture was weakly acidified with 1Nhydrochloric acid, extracted with methylene chloride. The organic layerwas washed with saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=9:1), to thereby obtain 1.25 gof the titled compound.

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.25(3H, s), 2.60(3H, s), 4.12(1H, dd),4.44(1H, t), 4.62(1H, d), 4.71-4.78(1H, m), 5.60-5.67(2H, m), 6.63(1H,d), 6.74(1H, d), 7.05(1H, s), 7.09-7.14(1H, m), 7.29-7.34(2H, m),7.45(1H, t), 7.61-7.63(2H, m), 7.82(1H, d), 8.20(1H, d)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in water, the solutionwas washed with diethyl ether, alkaline with saturated aqueous sodiumbicarbonate,and extracted with methylene chloride. The organic layer wasdried over anhydrous sodium sulfate, the solvent was evaporated underreduced pressure, to thereby obtain 886 mg of the titled compound(Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.69(2H, brs), 2.26(3H, s), 2.61(3H, s), 3.91(2H, q),4.46(1H, t), 4.53(1H, d), 5.76(1H, d), 6.64(1H, d), 6.73(1H, d),7.02(1H, s), 7.12(1H, dd), 7.30-7.35(2H, m), 7.46(1H, t), 7.60-7.65(2H,m), 7.85(1H, d), 8.19(1H, d)

Step 4

Preparation of1-[1-(2-toluoylmethy)-2-oxo-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (310 mg) was dissolved in tetrahydrofuran (50 ml),triphosgene (187 mg) was added under ice-cooling, triethylamine (161 μl)was added five times every 3 minutes,a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(730 mg) in tetrahydrofuran (23 ml) was added thereto, and the reactionmixture was allowed to come to room temperature, stirred for 2 hours.The reaction mixture was concentrated under reduced pressure, water (50ml) was added, extracted with methylene chloride. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography(chloroform:ethylacetate=10:1), to thereby obtain 483 mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.35(3H, t), 2.27(3H, s), 2.54(3H, s), 4.08-4.17(1H,m), 4.33(2H, q), 4.61(1H, t), 4.71(1H, d), 5.03-5.13(1H, m), 5.62(1H,d), 6.45(1H, d), 6.69(1H, d), 6.76(1H, d), 7.04(1H, s), 7.10-7.15(1H,m), 7.20-7.33(5H, m), 7.42(1H, t), 7.53-7.56(1H, m), 7.61-7.64(2H, m),7.80(1H, d), 7.91(1H, s), 8.22(1H, d)

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethy)-2-oxo-5-(2-pyridylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(466 mg) was dissolved in methanol (22 ml), aqueous lithium hydroxidemonohydrate (158 mg) solution (11 mg) and tetrahydrofuran (11 ml) wereadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inwater, the solution was washed with diethyl ether, acidified with 1Nhydrochloric acid, and extracted with methylene chloride. The organiclayer was washed with saturated brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure.Isopropyl ether was added to the residue for trituration, collected byfiltration, to thereby obtain 203 mg of the titled compound.

Melting point: 163-166° C.

¹H-NMR(CDCl₃) δ: 2.28(3H, s), 2.59(3H, s), 4.28(1H, dd), 4.60(1H, t),4.70(1H, d), 4.98-5.07(1H, m), 5.68(1H, d), 6.70(1H, d), 6.81(1H, d),7.06(1H, s), 7.11-7.16(1H, m), 7.33-7.39(3H, m), 7.46-7.51(2H, m),7.57-7.81 (5H, m), 8.18(1H, d), 8.27(1H, s), 8.36(1H, d), 12.82(1H, br)

MS(FAB)m/z: 592(MH)⁺

Example 106

Preparation of2-methyl-5-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea

Methyl 5-amino-2-methylbenzoate (223 mg) was dissolved intetrahydrofuran (30 ml), under ice-cooling triphosgene (135 mg) wasadded, triethylamine (116 μl) was added thereto five times every 3minutes, the mixture was stirred for 10 minutes at same temperature.Subsequently, a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(500 mg) in tetrahydrofuran (20 ml) was added dropwise, stirred for 30minutes at same temperature, and then stirred for 3 hours at roomtemperature. The reaction mixture was concentrated under reducedpressure, water (50 ml) was added, and extracted with methylenechloride. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=10:1), to thereby obtain 271 mgof the titled compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 2.39(3H, s), 2.50(3H, s), 2.52(3H, s),3.83(3H, s), 3.96(1H, dd), 4.34(1H, t), 4.43(1H, d), 4.79-4.89(1H, m),5.50(1H, d), 6.01(1H, d), 6.89(1H, brs), 7.03(1H, s), 7.03-7.35(6H, m),7.43(1H, t), 7.69(1H, d), 7.88(1H, d)

Step 2

Preparation of2-methyl-5-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-1-4-methylphenyl)urea(259 mg) was dissolved in methanol (14 ml), aqueous lithium hydroxidemonohydrate (91 mg) solution (7 ml) and tetrahydrofuran (7 ml) wereadded, the mixture was refluxed for one hour. The reaction mixture wasconcentrated under reduced pressure, 1N hydrochloric acid was added, andextracted with methylene chloride. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and a mixed solvent of diisopropyl ether and n-hexane wasadded to the residue for trituration, collected by filtration, tothereby obtain 180 mg of the titled compound (Yield: 73.4%).

Melting point: 174-177° C.

¹H-NMR(CDCl₃) δ: 1.08(9H, s), 2.40(3H, s), 2.50(3H, s), 2.53(3H, s),4.11(1H, dd), 4.41(1H, t), 4.54(1H, d), 4.78-4.84(1H, m), 5.47(1H, d),7.07(1H, s), 7.14-7.35(6H, m), 7.46(1H, t), 7.67-7.74(2H, m), 8.01(1H,s), 8.17(1H, dd), 10.80(1H, br)

MS(FAB)m/z: 585(MH⁺)

Example 107

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Referential Example 7 was suspended in methanol(20 ml), 1-bromo-3-methyl-2-butene (1.18 g) and potassium carbonate (997mg) were added, the mixture was stirred for 2 hours at room temperature.The reaction mixture was concentrated under reduced pressure, water (100ml) was added, and extracted with methylene chloride. The organic layerwas washed with saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure, to thereby obtain 1.85 g of the titled compound (Yield:71.4%).

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.68(3H, s), 1.71(3H, s), 2.28(3H, s),3.29-3.44(2H, m), 3.61-3.63(2H, m), 4.38-4.47(1H, m), 5.15 (1H, br),5.48(1H, d), 6.78(1H, s), 6.91(1H, d), 6.97(1H, d), 7.29(1H, brs)

MS (EI)m/z: 359(M⁺)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(965 mg) was suspended in toluene (14 ml), 2-bromo-2′-methylacetophenone(686 mg), 1N aqueous sodium hydroxide (7 ml) and tetran-butylammoniumbromide (20 mg) were added, and the mixture was stirred overnight atroom temperature. The reaction mixture was weakly acidified with 1Nhydrochloric acid, extracted with methylene chloride. The organic layerwas washed with saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=10:1), to thereby obtain 782 mgof the titled compound.

¹H-NMR(CDCl₃) δ: 1.39(9H, s), 1.67(3H, s), 1.70(3H, s), 2.27(3H, s),2.48(3H, s), 3.20-3.36(2H, m), 3.49-3.52 (2H, m), 4.46-4.50 (1H, m),4.67(1H, d), 5.05 (1H, br), 5.34(1H, d), 5.54 (1H, d), 6.86-6.92(2H, m),6.98 (1H, d), 7.23-7.27 (2H, m), 7.40 (1H, t), 7.68-7.71 (1H, m)

MS(EI)m/z: 491(M⁺)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(780 mg) was suspended in 4N HCl-dioxane (10 ml), the suspension wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in water, washed withdiethyl ether, alkalified with saturated aqueous sodium bicarbonate, andextracted with methylene chloride. The organic layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, to thereby obtain 493 mg of the titled compound (Yield:79.4%).

¹H-NMR(CDCl₃) δ: 1.68(3H, s), 1.70(3H, s), 1.70(2H, br), 2.28(3H, s),2.51(3H, s), 3.12-3.25(2H, m), 3.48-3.55(2H, m), 3.62(1H, dd), 4.57(1H,d), 5.07(1H, m), 5.49(1H, d), 6.89-6.92(2H, m), 6.99(1H, d),7.26-7.30(2H, m), 7.38-7.44(1H, m), 7.72-7.75(1H, m)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (221 mg) was dissolved in tetrahydrofuran (20 ml),under ice-cooling triphosgene (134 mg) was added, triethylamine (115 μl)was added thereto five times every 3 minutes,a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(477 mg) in tetrahydrofuran (20 ml) was added dropwise thereto, and themixture was stirred for 30 minutes at same temperature and subsequentlystirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, water (50 ml) was added, andextracted with methylene chloride. The organic layer was washed withsaturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel columnchromatography(chloroform:ethyl acetate=10:1), to thereby obtain 316 mgof the titled compound.

¹H-NMR(CDCl₃) δ: 1.34(3H, t), 1.66(3H, s), 1.68(3H, s), 2.28(3H, s),2.44(3H, s), 3.30-3.45(2H, m), 3.53(2H, d), 4.31(2H, q), 4.75(1H, d),4.74-4.84(1H, m), 5.07(1H, m), 5.39(1H, d), 6.28(1H, d), 6.91-6.94(2H,m), 7.02(1H, d), 7.14(1H, s), 7.18-7.26(3H, m), 7.37(1H, t), 7.52(1H,d), 7.61-7.66(2H, m), 7.92(1H, t)

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(310 mg) was dissolved in methanol (16 ml), aqueous lithium hydroxidemonohydrate (112 mg) solution (8 ml) and tetrahydrofuran (8 ml) wereadded, and the mixture was refluxed for 50 minutes. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inwater (150 ml), washed with diethyl ether, acidified with 1Nhydrochloric acid, and extracted with methylene chloride. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure, and a mixed solvent of diisopropylether and n-hexane were added to the residue for trituration, collectedby filtration, to thereby obtain 230 mg of the titled compound (Yield:78.3%).

Melting point: 129-131° C.

¹H-NMR(CDCl₃) δ: 1.68(3H, s), 1.71(3H, s), 2.29(3H, s), 2.50(3H, s),3.36(1H, t), 3.55-3.60(3H, m), 4.69-4.76(2H, m), 5.11(1H, brs), 5.40(1H,d), 6.93-6.97(2H, m), 7.05(1H, d), 7.26-7.46(5H, m), 7.57(1H, d),7.66(1H, d), 7.73(1H, s), 8.22(1H, s), 8.38(1H, d), 10.96(1H, br)

MS(FAB)m/z: 555(MH)⁺

Example 108

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-isovaleryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(1-(2-toluoylmethyl)-2-oxo-5-isovaleryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(400 mg) obtained from Step 1 of Example 93 was suspended in1,2-dichloroethane (10 ml), isovaleryl chloride (104 μl) and pyridine(70 μl) were added, and the mixture was refluxed for 1 hour and 30minutes. Water and methylene chloride were added to the reactionmixture, separated, and the organic layer was successively washed with1N hydrochloric acid and saturated aqueous sodium bicarbonate, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 296 mg ofthe titled compound.

¹H-NMR(CDCl₃) δ: 0.80-0.94(7H, m), 1.35(3H, t), 2.32-2.42(2H, m),2.39(3H, s), 2.44(3H, s), 4.32(2H, q), 4.73(1H, t), 4.88-4.94(2H, m),5.20(1H, d), 6.39(1H, d), 7.00(1H, s), 7.10-7.30(5H, m), 7.39(1H, t),7.63-7.68(4H, m), 7.77(1H, brs), 7.87(1H, s)

Step 2

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-isovaleryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-isovaleryl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(296 mg) was dissolved in methanol (14 ml), aqueous lithium hydroxidemonohydrate (62 mg) solution (7 ml) and tetrahydrofuran (7 ml) wereadded, and the mixture was refluxed for 45 minutes. The reaction mixturewas concentrated under reduced pressure, 1N hydrochloric acid was added,and extracted with methylene chloride. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. Isopropyl ether was added to theresidue for trituration, collected by filtration, to thereby obtain 160mg of the titled compound.

Melting point: 202-205° C.

¹H-NMR(DMSO-d₆) δ: 0.79(3H, d), 0.84(3H, d), 1.86-2.09(3H, m), 2.39(3H,s), 2.50(3H, s), 3.58-3.60(1H, m), 4.46-4.56(2H, m), 5.18(1H, d),5.26(1H, d), 6.74(1H, d), 7.16-7.39(6H, m), 7.47-7.53(3H, m), 7.94 (1H,d), 8.01(1H, t), 9.00(1H, s), 12.80(1H, brs)

Example 109

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Referential Example 7 was suspended in1,2-dichloroethane (40 ml), 3,3-dimethylbutanoyl chloride (1.07 g) andpyridine (627 mg) were added, and the mixture was refluxed for 2 hours.Water was added to the reaction mixture, separated, the organic layerwas washed with saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure, to thereby obtain 2.53 g of the titled compound (Yield:90.1%).

¹H-NMR(CDCl₃) δ: 0.89(9H, s), 1.41(9H, s), 1.93(2H, s), 2.39(3H, s),3.80-3.81(1H, m), 4.53-4.56(2H, m), 5.40(1H, br), 6.94(1H, s),7.07-7.09(2H, brs), 7.60(1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine2-Oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.52 g) was suspended in toluene (36 ml), 2-bromo-2′-methylacetophenone(1.65 g), 1N aqueous sodium hydroxide (18 ml) and tetra n-butylammoniumbromide (40 mg) were added thereto, and the mixture was stirred for 1hour and 50 minutes at room temperature. Methylene chloride (100 ml) wasadded to the reaction mixture, separated, the organic layer was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, the residue was purifiedby silica gel column chromatography(chloroform:ethyl acetate=30:1), tothereby obtain 1.47 g of the titled compound.

¹H-NMR(CDCl₃) δ: 0.95(9H, s), 1.40(9H, s), 2.01(1H, d), 2.10(1H, d),2.37(3H, s), 2.53(3H, s), 3.82(1H, dd), 4.44-4.57(2H, m), 4.69(1H, d),5.28(1H, d), 5.48(1H, d), 7.04-7.12(2H, m), 7.26-7.33(3H, m), 7.44(1H,t), 7.73(1H, d)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was suspended in4N HCl-dioxane (10 ml), the suspension wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, saturated aqueous sodium bicarbonate was added,and extracted with methylene chloride. The organic layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, to thereby obtain 741 mg of the titled compound (Yield:91.6%).

¹H-NMR(CDCl₃) δ: 0.94(9H, s), 1.60 (2H, br), 1.98(1H, d), 2.06(1H, d),2.38(3H, s), 2.56(3H, s), 3.63-3.70(2H, m), 4.40-4.54(1H, m), 4.51(1H,d), 5.46(1H, d), 7.01(1H, s), 7.05-7.12(2H, m), 7.25-7.34(2H, m),7.45(1H, t), 7.76(1H, d)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (236 mg) was dissolved in tetrahydrofuran (40 ml),under ice-cooling triphosgene (140 mg) was added and triethylamine (120μl) was added thereto five times every 3 minutes, a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(536 mg) in tetrahydrofuran (10 ml) was subsequently added, the mixturewas stirred for 30 minutes at same temperature,and additionally stirredfor 2 hours at room temperature. The reaction mixture was poured intowater (400 ml),extracted with methylene chloride (50 ml), and theorganic layer was dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain479 mg of the titled compound

¹H-NMR(CDCl₃) δ: 0.97(9H, s), 1.35(3H, t), 2.05(1H, d), 2.17(1H, d),2.38(3H, s), 2.48(3H, s), 3.85(1H, dd), 4.32(2H, q), 4.63(1H, t),4.71(1H, d), 4.84-4.91(1H, m), 5.32(1H, d), 6.31(1H, d), 7.04(1H, s),7.13(2H, s), 7.21-7.28(3H, m), 7.37-7.43(2H, m), 7.58-7.71(3H, m),7.89(1H, t)

Step 5

Preparation of 3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(442 mg) was dissolved in methanol (20 ml), aqueous lithium hydroxidemonohydrate (151 mg) solution (10 ml) and tetrahydrofuran (10 ml) wereadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, 1N hydrochloric acid was addedto the residue, extracted with methylene chloride. The solvent wasevaporated under reduced pressure, diisopropyl ether was added to theresidue for trituration, collected by filtration, to thereby obtain 324mg of the titled compound as colorless powder (Yield: 77.1%).

¹H-NMR(CDCl₃) δ: 0.98(9H, s), 2.04(1H, d), 2.10(1H, d), 2.39(3H, s),2.51(3H, s), 3.92(1H, dd), 4.65-4.80(3H, m), 5.29(1H, d), 7.05(1H, s),7.16(2H, s), 7.26-7.36(4H, m), 7.47(1H, t), 7.57(1H, d), 7.70-7.72(2H,m), 8.21(1H, brs), 8.32(1H, d), 10.00(1H, br)

MS(FAB)m/z: 607(M+Na)⁺

Example 110

Preparation of2-chloro-5-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-chlorophenyl)urea

Methyl 5-amino-2-chlorobenzoate (223 mg) was dissolved intetrahydrofuran (50 ml), triphosgene (135 mg) was added underice-cooling, triethylamine (116 μl) was added thereto five times every 3minutes, the mixture was stirred for 10 minutes at same temperature. Asolution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(500 mg) in tetrahydrofuran (10 ml) was added dropwise, the resultantmixture was stirred for 30 minutes at same temperature and additionallystirred for 2 hours at room temperature. The reaction mixture was pouredinto water (400 ml), extracted with methylene chloride. The organiclayer was washed with 1N hydrochloric acid, dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography(n-hexane:ethylacetate=2:1), to thereby obtain 756 mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 2.40(3H, s), 2.54(3H, s), 3.84(3H, s),3.84-3.90(1H, m), 4.34-4.45(2H, m), 4.84-4.94(1H, m), 5.56(1H, d),6.65(1H, d), 7.01(1H, s), 7.12-7.31(6H, m), 7.43(1H, t), 7.49(1H, s),7.67(1H, d), 7.90(1H, d)

Step 2

Preparation of2-chloro-5-[3-[1-(2-toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-chlorophenyl)urea(691 mg) was dissolved in methanol (30 ml), aqueous lithium hydroxidemonohydrate (234 mg) solution (15 ml) and tetrahydrofuran (15 ml) wereadded, the mixture was refluxed for one hour. The reaction mixture wasconcentrated under reduced pressure, 1N hydrochloric acid was added, andextracted with methylene chloride. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and diisopropyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 437 mg of thetitled compound.

Melting point: 178-180° C.

¹H-NMR(CDCl₃) δ: 1.07(9H, s), 2.39(3H, s), 2.53(3H, s), 4.03-4.10(1H,m), 4.41(1H, t), 4.55(1H, d), 4.78-4.85(1H, m), 5.51(1H, d), 7.06(1H,s), 7.14-7.35(6H, m), 7.46(1H, t), 7.62 (1H, d), 7.70-7.73(1H, m),7.96(1H, s), 8.14(1H, dd), 11.00(1H, br)

MS(FAB)m/z: 605(MH⁺)

Example 111

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Referential Example 7 was suspended in1,2-dichloroethane (40 ml), acetyl chloride (0.56 ml) and pyridine (0.64ml) were added thereto, the mixture was refluxed for 2 hours. Water (100ml) was added, extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium bicarbonate, dried over anhydroussodium sulfate, the solvent was evaporated under reduced pressure, anddiisopropyl ether was added to the residue for trituration, collectedlyfiltration, to thereby obtain 1.33 g of the titled compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 1.79(3H, s), 2.39(3H, s), 3.80-3.85(1H,m), 4.52-4.64(2H, m), 5.45(1H, d), 6.97(1H, s), 7.14(1H, d), 7.22(1H,d), 7.81(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.30 g) was suspended in toluene (18 ml), 2-bromo-2′-methylacetophenone(1.00 g), 1N aqueous sodium hydroxide (9 ml) and tetra n-butylammoniumbromide (20 mg) were added thereto, and the mixture was stirred for 2hours at room temperature. The reaction mixture was weakly acidifiedwith 1N hydrochloric acid, extracted with methylene chloride. Theorganic layer was washed with saturated aqueous sodium bicarbonate,dried over anhydrous sodium sulfate, the solvent was evaporated underreduced pressure. Diisopropyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 1.45 g of thetitled compound (Yield: 79.7%).

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.89(3H, s), 2.38(3H, s), 2.47(3H, s),3.70-3.80(1H, m), 4.51-4.60(2H, m), 5.00 (1H, d), 5.20 (1H, d), 5.47(1H,brs), 7.06(1H, s), 7.12 (2H, s), 7.26-7.32(2H, m), 7.43(1H, t), 7.73(1H, d)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in water, washed withdiethyl ether, alkalified with saturated aqueous sodium bicarbonate, andextracted with methylene chloride. The organic layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, to thereby obtain 820 mg of the titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.61(2H, brs), 1.85(3H, s), 2.39(3H, s), 2.50(3H, s),3.60-3.76(2H, m), 4.54(1H, t), 4.97(1H, d), 5.21(1H, d), 7.04(1H, s),7.09 (2H, s), 7.30(2H, t), 7.44(1H, t), 7.76(1H, d)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (386 mg) was dissolved in tetrahydrofuran (60 ml),under ice-cooling triphosgene (233 mg) was added, triethylamine (201 μl)was added thereto five times every 3 minutes, a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-acethyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(777 mg) in tetrahydrofuran (18 ml) was subsequently added, and themixture was allowed to come to room temperature and stirred for 4 hours.The reaction mixture was concentrated under reduced pressure, water (50ml) was added, and extracted with methylene chloride. The organic layerwas successively washed with 1N hydrochloric acid and saturated aqueoussodium bicarbonate, dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure, to thereby obtain 670 mg of thetitled compound.

¹H-NMR(CDCl₃) δ: 1.34(3H, t), 2.00(3H, s), 2.33(3H, s), 2.40(3H, s),3.83(1H, dd), 4.32(2H, q), 4.73-4.98(3H, m), 5.40(1H, d), 6.52(1H, d),7.10-7.38(7H, m), 7.61-7.76(3H, m), 7.90(1H, t), 8.25(1H, s)

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(670 mg) was dissolved in methanol (32 ml), aqueous lithium hydroxidemonohydrate (253 mg) solution (16 ml) and tetrahydrofuran (16 ml) wereadded, and the mixture was refluxed for 45 minutes, the reaction mixturewas concentrated under reduced pressure, the residue was dissolved inwater (150 ml), the solution was washed with diethyl ether, acidifiedwith 1N hydrochloric acid, and extracted with methylene chloride. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,diisoproryl ether was added to the residue for trituration, collected byfiltration, to thereby obtain 370 mg of the titled compound.

Melting point: 184-187° C.

¹H-NMR(CDCl₃) δ: 1.92(3H, s), 2.40(3H, s), 2.44(3H, s), 3.76(1H, dd),4.65(1H, t), 4.84(1H, dd), 4.93(1H, d), 5.30(1H, d), 7.10-7.43(10H, m),7.60(1H, d), 7.76(1H, m), 7.88(1H, s), 12.83(1H, br)

IR(KBr)cm⁻¹:3376, 1713, 1647, 1608, 1560, 1221, 756

MS(FAB)m/z: 529(MH⁺)

Example 112

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Referential Example 7 was suspended in1,2-dichloroethane (40 ml), 3,3-dimethylacryloyl chloride (941 mg) andpyridine (626 mg) were added, the mixture was refluxed for one hour. Thereaction mixture was allowed to cool, water (100 ml) was added, andextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure.Isopropylether was added to the residue for trituration, collected byfiltration, to thereby obtain 1.62 g of the titled compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 1.67(3H, s), 2.10(3H, s), 2.39(3H, s),3.99(1H, dd), 4.42-4.57(2H, m), 5.20(1H, brs), 5.47(1H, d), 6.96(1H, s),7.03(2H, s), 8.27(1H, br)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.54 g) was suspended in toluene (22 ml), 2-bromo-2′-methylacetophenone(1.05 g), 1N aqueous sodium hydroxide (11 ml) and tetra n-butylammoniumbromide (25 mg) were added, and the mixture was stirred for 4 hours atroom temperature. The reaction mixture was acidified with 1Nhydrochloric acid, extracted with methylene chloride. The organic layerwas washed with saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=10:1), to thereby obtain 2.26 gof the titled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.68(3H, s), 2.13(3H, s), 2.36(3H, s),2.49(3H, s), 3.86(1H, dd), 4.39(1H, t), 4.56-4.63(1H, m), 4.94(1H, d),5.17(1H, d), 5.28(1H, brs), 5.50(1H, d), 7.01-7.04(3H, m), 7.26-7.31(2H,m), 7.42(1H, t), 7.72(1H, d)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in water, the solutionwas washed with diethyl ether, alkalified with saturated aqueous sodiumbicarbonate, and extracted with methylene chloride. The organic layerwas dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure, to thereby obtain 694 mg of the titled compound(Yield: 86.5%).

¹H-NMR(CDCl₃) δ: 1.68(3H, s), 1.89(2H, br), 2.13(3H, s), 2.37(3H, s),2.52(3H, s), 3.68-3.78(2H, m), 4.42(1H, t), 4.77(1H, d), 5.25(1H, brs),5.34(1H, d), 7.02-7.14(3H, m), 7.27-7.32(2H, m), 7.43(1H, t), 7.75(1H,d)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (290 mg) was dissolved in tetrahydrofuran (60 m),under ice-cooling triphosgene (175 mg) was added, triethylamine (151 μl)was added thereto five times every 3 minutes,a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(647 mg) in tetrahydrofuran (5 ml) was subsequently added, and themixture was allowed to come to room temperature and stirred for 2 hoursand 40 minutes. The reaction mixture was concentrated under reducedpressure, water was added, and extracted with methylene chloride. Theorganic layer was successively washed with 1N hydrochloric acid andsaturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel columnchromatography(chloroform:ethyl acetate=5:1), to thereby obtain 373 mgof the titled compound.

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(340 mg) was dissolved in methanol (16 ml), aqueous lithium hydroxidemonohydrate (120 mg) solution (8 ml) and tetrahydrofuran (8 ml) wereadded, and the mixture was refluxed for 50 minutes. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inwater (150 ml), the solution was washed with diethyl ether, acidifiedwith 1N hydrochloric acid, and extracted with methylene chloride. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and diisoproryl ether was added to the residue for trituration,collected by filtration, to thereby obtain 223 mg of the titled compound(Yield: 68.8%).

Melting point: 240-242° C.

¹H-NMR(DMSO-d₆) δ: 1.63(3H, s), 2.04(3H, s), 2.36(3H, s), 2.37(3H, s),3.64(1H, m), 4.34(1H, t), 4.55(1H, m), 5.26(1H, s), 5.35(1H, s),6.78(1H, d), 7.14-7.18(2H, m), 7.31-7.37(4H, m), 7.45-7.53(4H, m),7.91(1H, d), 8.01(1H, s), 9.03(1H, s), 12.80(1H, br)

MS(FAB)m/z: 569(MH⁺)

Example 113

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Referential Example 7 was suspended in1,2-dichloroethane (40 ml), 2-furancarbonyl chloride (1.05 g) andpyridine (626 mg) were added thereto, the mixture was refluxed for 2hours. Water (100 ml) was added to the reaction mixture, extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate, dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, and diisopropyl ether was added tothe residue for trituration, collected by filtration, to thereby obtain2.15 g of the titled compound (Yield: 77,4%).

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.39(3H, s), 4.09(1H, dd), 4.46(1H, t),4.60-4.68(1H, m), 5.49(1H, d), 5.99(1H, br), 6.23(1H, dd), 6.98-7.03(3H,m), 7.26(1H, m), 7.69(1H, s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.50 g) was suspended in toluene (20 ml), 2-bromo-2′-methylacetophenone(995 mg), 1N aqueous sodium hydroxide (10 ml) and tetra n-butylammoniumbromide (20 mg) were added, and the mixture was stirred for 2 hours atroom temperature. The reaction mixture was weakly acidified with 1Nhydrochloric acid, and extracted with methylene chloride. The organiclayer was washed with saturated aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=20:1), to thereby obtain 1.55 gof the titled compound (Yield: 76.9%).

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 2.38(3H, s), 2.51(3H, s), 4.05-4.14(1H,m), 4.18(1H, t), 4.65-4.77(2H, m), 5.38(1H, d), 5.57(1H, d), 6.12(1H,br), 6.24(1H, brs), 6.98(2H, s), 7.11(1H, s), 7.26-7.30(3H, s), 7.42(1H,t), 7.75(1H, d)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was dissolved in 4N HCl-dioxane (10 ml), the solution wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in water, the solutionwas washed with diethyl ether, alkalified with saturated aqueous sodiumbicarbonate, and extracted with methylene chloride. The organic layerwas dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure, to thereby obtain 875 mg of the titled compound(Yield: 100%).

¹H-NMR(CDCl₃) δ: 2.20(3H, s), 2.27(3H, s), 2.30(2H, br), 4.40-4.47(1H,m), 4.52-4.58(1H, m), 5.02(1H, d), 5.14(1H, t), 5.29(1H, d), 6.15(2H,brs), 6.84(1H, d), 6.94(1H, d), 7.06(1H, d), 7.16-7.25(4H, m), 7.75(1H,d)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (373 mg) was dissolved in tetrahydrofuran (60 ml),under ice-cooling triphosgene (225 mg) was added, triethylamine (194 μl)was added thereto five times every 3 minutes, a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(856 mg) in tetrahydrofuran (15 ml) was added thereto, the mixture wasallowed to come to room temperature and stirred overnight. The reactionmixture was concentrated under reduced pressure, water (50 ml) was addedto the residue, extracted with methylene chloride. The organic layer wasdried over anhydrous sodium sulfate, the solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography(chloroform:ethyl acetate=10:1), to thereby obtain 447 mgof the titled compound.

¹H-NMR(CDCl₃) δ: 1.35(3H, t), 2.36(3H, s), 2.41(3H, s), 4.05-4.13(1H,m), 4.34(2H, d), 4.73(1H, t), 4.91(1H, d), 5.01-5.11(1H, m), 5.20(1H,d), 5.78(1H, brs), 6.19-6.21(1H, m), 6.65(1H, d), 7.05-7.36(7H, m),7.41(1H, d), 7.63-7.70(2H, m), 7.78(1H, d), 7.89(1H, brs), 7.94(1H, t)

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(429 mg) was dissolved in methanol (22 ml), aqueous lithium hydroxidemonohydrate (148 mg) solution (11 ml) and tetrahydrofuran (11 ml) wereadded, and the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inwater (150 ml), the solution was washed with diethyl ether, acidifiedwith 1N hydrochloric acid, and extracted with methylene chloride. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. Isoproryl ether was added to the residue fortrituration,collected by filtration, to thereby obtain 237 mg of thetitled compound.

Melting point: 219-221° C.

¹H-NMR(CDCl₃) δ: 2.40(3H, s), 2.45(3H, s), 4.08(1H, m), 4.50(1H, t),4.79(1H, d), 4.92-5.01(1H, m), 5.29(1H, d), 6.03(1H, br), 6.25(1H, brs),6.76(1H, d), 7.04(2H, s), 7.13(1H, s), 7.25-7.31(4H, m), 7.38-7.44(1H,m), 7.61(1H, d), 7.73-7.81(2H, m), 7.88(1H, t), 8.68(1H, s), 11.60(1H,br)

MS(FAB)m/z: 581(MH⁺)

Example 114

Preparation of3-[3-[1-(furan-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(furan-2-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

60% Sodium hydride (320 mg) was suspended in tetrahydrofuran (30 ml),under ice-cooling2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) obtained from Step I of Example 89, and the mixture was stirredfor 30 minutes. Bromomethyl(furan-2-yl)ketone (1.89 g) was addeddropwise thereto, stirred for 2 hours at room temperature. The reactionmixture was concentrated under reduced pressure, water (100 ml) andethyl acetate (100 ml) were added, and separated into aqueous layer andorganic layer. The aqueous layer was acidified with 1N hydrochloricacid, extracted with ethyl acetate. The extract was combined with theformer organic layer. The combined extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, subsequently, purified bysilica gel column chromatography(chloroform:ethyl acetate=10:1), tothereby obtain 550 mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.39(9H, s), 2.36(3H, s), 3.90(1H, dd),4.24(1H, t), 4.39(1H, d), 4.52(1H, m), 5.47 (1H, d), 5.56(1H, d),6.62(1H, dd), 7.07-7.14(3H, m), 7.37(1H, d), 7.64(1H, d)

Step 2

Preparation of1-(furan-2-yl)carbonylmethyl-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(Furan-2-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was suspended in ethanol (10 ml), concentrated hydrochloricacid (2 ml) was added, and the mixture was stirred for one hour at 50°C. The reaction mixture was concentrated under reduced pressure, theresidue was dissolved in etheyl acetate, successively washed withsaturated aqueous sodium bicarbonate and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, diethyl ether was added to the residue for trituration,collected by filtration, to thereby obtain 373 mg of the titledcompound.

¹H-NMR(CDCl₃) δ: 1.02(9H, s), 2.37(3H, s), 2.38(2H, br), 3.77(2H, m),4.30-4.38(1H, m), 4.35(1H, d), 5.65(1H, d), 6.62(1H, dd), 7.04-7.15(3H,m), 7.38(1H, d), 7.65(1H, d)

Step 3

Preparation of1-[1-(furan-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (171 mg) was dissolved in tetrahydrofuran (20 ml),under ice-cooling triphosgene (104 mg) was added, triethylamine (90 μl)was added thereto five times every 3 minutes,a suspension of1-(furan-2-yl)carbonylmathyl-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(362 mg) in tetrahydrofuran (10 ml), and the mixture was allowed to cometo room temperature and stirred for 2 hours. The reaction mixture wasconcentrated under reduced pressure, water (50 ml) was added to theresidue, and extracted with methylene chloride. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography(chloroform:ethylacetate=9:1), to thereby obtain 192 mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.04(9H, s), 1.36(3H, t), 2.38(3H, s), 3.94(1H, dd),4.30-4.46(2H, m), 4.34(2H, q), 4.78-4.85(1H, m), 5.60(1H, d), 6.02(1H,d), 6.59(1H, dd), 7.02-7.19(4H, m), 7.26-7.33(1H, m), 7.36(1H, dd),7.58-7.69(3H, m), 7.90(1H, t)

Step 4

Preparation of3-[3-[1-(furan-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(Furan-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(187 mg) was dissolved in methanol (8.8 ml), aqueous lithium hydroxidemonohydrate (68.3 mg) solution (4.4 ml) and tetrahydrofuran (4.4 ml)were added, the mixture was refluxed for one hour. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inwater (50 ml), the solution was washed with diethyl ether, acidifiedwith 1N hydrochloric acid,and extracted with methylene chloride. Theorganic layer was dried over anhydrous magnesium sulfate, the solventwas evaporated under reduced pressure, and diisoproryl ether was addedto the residue for trituration, collected by filtration, to therebyobtain 110 mg of the titled compound.

Melting point: 202-204° C.

¹H-NMR(CDCl₃) δ: 1.04(9H, m), 2.37(3H, s), 3.90(1H, dd), 4.32(1H, t),4.45(1H, d), 4.75-4.82(1H, m), 5.51(1H, d), 6.55(1H, d), 6.62(1H, dd),7.06(1H, s), 7.09-7.18(2H, m), 7.27(1H, t), 7.33-7.35(2H, m), 7.61(1H,d), 7.65-7.66(1H, m), 7.80(1H, d), 7.84(1H, m), 8.58(1H, s)

IR(KBr)cm⁻¹:3389, 1702, 1641, 1555

Example 115

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) was suspended in 1,2-dichloroethane (20 ml), cyclohexylcarbonylchloride (1.21 g) and pyridine (652 mg) were added, and the mixture wasrefluxed for 1 hour and 30 minutes. Water (100 ml) was added to thereaction mixture, extracted with methylene chloride. The organic layerwas washed with water, dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure, and n-hexane was added tothe residue for trituration, collected by filtration, to thereby obtain2.04 g of the titled compound (Yield: 74.2%).

¹H-NMR(CDCl₃) δ: 0.86-1.73(10H, m), 1.41(9H, s), 2.00(1H, m), 2.40(3H,s), 3.74-3.78(1H, m), 4.52-4.55(2H, m), 5.40(1H, m), 6.95(1H, s),7.10(2H, s), 7.76(1H, d)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) was suspended in toluene (28 ml), 2-bromo-2′-methylacetophenone(1.28 g), 1N aqueous sodium hydroxide (14 ml) and tetra n-butylammoniumbromide (20 mg) were added, and the mixture was stirred for 2 hours atroom temperature. The reaction mixture was acidified with 1Nhydrochloric acid, extracted with ethyl acetate. The organic layer wassuccessively washed with saturated aqueous sodium bicarbonate andsaturated brine, dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure, and diisopropyl was added to theresidue for trituration, collected by filtration, to thereby obtain 2.15g of the titled compound (Yield: 80.7%).

¹H-NMR(CDCl₃) δ: 0.94-1.81(10H, m), 1.40(9H, s), 2.13-2.17(1H, m),2.39(3H, s), 2.51(3H, s), 3.79(1H, dd), 4.48(1H, t), 4.52-4.61(1H, m),4.81(1H, d), 5.27(1H, d), 5.48(1H, d), 7.07-7.34(5H, m), 7.44(1H, t),7.76(1H, d)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension wasstirred for one hour at 50° C. The reaction mixture was concentratedunder reduced pressure, the residue was dissolved in methylene chloride(100 ml), the solution was successively washed with saturated aqueoussodium bicarbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, a mixedsolvent of n-hexane and diisopropyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 700 mg of thetitled compound (Yield: 86.2%).

¹H-NMR(CDCl₃) δ: 0.88-1.73(12H, m), 2.13(1H, m), 2.40(3H, s), 2.55(3H,s), 3.60-3.67(2H, m), 4.48(1H, t), 4.59(1H, d), 5.45(1H, d), 7.04(1H,s), 7.10(1H, d), 7.12(1H, d), 7.32(2H, t), 7.45(1H, t), 7.79(1H, d)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (252 mg) was dissolved in tetrahydrofuran (40 ml),triphosgene (152 mg) was added under ice-cooling, subsequently,triethylamine (132 μl) was added five times every 3 minutes, a solutionof1-(2-toluoylmethyl)-2-oxo-3-amino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(600 mg) in tetrahydrofuran (20 ml), and the reaction mixture wasallowed to come to room temperature and additionally stirred for 2hours. The reaction mixture was concentrated under reduced pressure,water (50 ml) was added to the residue, extracted with methylenechloride. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 500 mg ofthe titled compound.

¹H-NMR(CDCl₃) δ: 1.06-1.84(10H, m), 1.35(3H, t), 2.23(1H, m), 2.39(3H,s), 2.44(3H, s), 3.84(1H, dd), 4.34(2H, dd), 4.59(1H, t), 4.84-4.91(1H,m), 4.88(1H, d), 5.26(1H, d), 6.34(1H, d), 7.06(1H, s), 7.14-7.31(5H,m), 7.38(1H, t), 7.67(3H, t), 7.79(1H, brs), 7.92(1H, s)

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxidemonohydrate (168 mg) solution (12 ml) and tetrahydrofuran (12 ml) wereadded, and the mixture was refluxed for 30 minutes. The reaction mixturewas concentrated under reduced pressure, the residue was dissolved inwater (50 ml), the solution was washed with diethyl ether, acidifiedwith 1N hydrochloric acid, and extracted with methylene chloride (50ml).The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and isoproryl ether was added to the residue for trituration, collectedby filtration, to thereby obtain 240 mg of the titled compound.

Melting point: 183-185° C.

¹H-NMR(CDCl₃) δ: 0.97-1.79(10H, m), 2.10-2.30(1H, m), 2.41(3H, s),2.48(3H, s), 2.59(1H, t), 3.77(1H, dd), 4.53(1H, t), 4.77-4.87(1H, m),4.92(1H, d), 5.23(1H, d), 6.67(1H, d), 7.10(1H, s), 7.16(2H, s),7.24-7.35(3H, m), 7.42-7.47(1H, m), 7.59(1H, d), 7.77(2H, t), 7.88(1H,s), 8.71(1H, s)

MS(FAB)m/z: 597(MH⁺)

Example 116

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.05 g) obtained from Step 1 of Referential Example 10 was dissolved intoluene (14 ml), 2-bromo-2′-methylacetophenone (723 mg), 1N aqueoussodium hydroxide (7 ml) and tetra n-butylammonium bromide (20 mg) wereadded, and the mixture was stirred overnight at room temperature. Thereaction mixture was separated into organic layer and aqueous layer, theorganic layer was dried over anhydrous magnesium sulfate, the solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography(n-hexane:ethyl acetate=5:1), to therebyobtain 557 mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.63-2.05(6H, m), 2.26(3H, s),2.50-2.52(3H, s), 3.13-3.26(1H, m), 3.63-3.75(1H, m), 3.73-3.96(1H, m),4.47-4.56(1H, m), 4.63(1H, dd), 5.32(1H, t), 5.54(1H, d), 5.61-5.90(2H,m), 6.91(1H, s), 6.93-7.13(2H, m), 7.23-7.29(2H, m), 7.37-7.43(1H, m),7.68-7.71(1H, m)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.30 g) was dissolved in methanol (10 ml), 10% palladium carbon (0.10g) was added, the mixture was stirred for 2 hours under hydrogenatmosphere. Palladium carbon was removed by filtration, the filtrate wasconcentrated under reduced pressure, to thereby obtain 0.29 g of thetitled compound (Yield 96%).

¹H-NMR(CDCl₃) δ: 1.21-2.09(19H, m), 2.27(3H, s), 2.52(3H, s),3.11-3.29(2H, m), 3.50-3.58(1H, m), 4.44-4.61(2H, m), 5.37(1H, d),5.56(1H, brd), 6.92-7.74(7H, m)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.28 g) was dissolved in 4N HCl-dioxane (5 ml), the solution wasstirred for one hour at 60° C. The reaction mixture was concentratedunder reduced pressure, the residue was neutralized with saturatedaqueous sodium bicarbonate, and extracted with methylene chloride. Theorganic layer was dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, to thereby obtain 0.22 g of thetitled compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.22-2.09(10H, m), 2.28(3H, s), 2.55(3H, s),3.12-3.39(3H, m), 3.62(3H, br), 4.47(1H, d), 5.51(1H, d), 6.91-7.77(7H,m)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (100 mg) was dissolved in tetrahydrofuran (5 ml),the solution was cooled on ice, triphosgene (65 mg) was added thereto atinternal temperature 5° C., triethylamine (220 mg) was added thereto at3 minutes intervals, the mixture was allowed to come to room temperatureand stirred for 10 minutes. A solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(820 mg) in tetrahydrofuran (5 ml) was added, additionally stirred forone hour. Water was added to the reaction mixture, extracted withmethylene chloride. The organic layer was successively washed with waterand saturated brine, dried over anhydrous sodium sulfate, the solventwas evaporated under reduced pressure, the residue was purified bysilica gel column chromatography(n-hexane:ethyl acetate=3:1), to therebyobtain 265 mg of the titled compound (Yield 81%).

¹H-NMR(CDCl₃) δ: 1.18-1.96 (13H, m), 2.28 (3H, s), 2.46 (3H, s),3.09-3.18(1H, m), 3.34-3.41(1H, m), 3.55-3.61(1H, m), 4.30(2H, q), 4.72(1H, d), 4.75-4.86 (1H, m), 5.39(1H, d), 6.51(1H, brd), 6.93-7.93(12H,m)

Step 5

Preparation of3-[3-[1-(2-toluoylmethyl)-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(0.26 g) was dissolved in a mixed solvent of tetrahydrofuran (5 ml) andethanol (5 ml), aqueous lithium hydroxide monohydrate (0.18 g) solution(5 ml) was added, and the mixture was stirred at room temperature for 3hour. The reaction mixture was concentrated under reduced pressure, theresidue was weakly acidified with 1N hydrochloric acid, and extractedwith chloroform. The organic layer was successively washed with waterand saturated brine, the solvent was evaporated under reduced pressure,and diisoproryl ether was added to the residue for trituration,collected by filtration, to thereby obtain 0.20 g of the titled compoundas yellow-white powder (Yield: 82%)

¹H-NMR(CDCl₃) δ: 1.19-2.05(10H, m), 2.29(3H, s), 2.53(3H, s),3.10-3.20(1H, m), 3.34-3.42(1H, m), 3.75-3.81(1H, m), 4.59-4.75(2H, m),5.41(1H, d), 6.92-7.75(11H, m), 8.24-8.41(2H, m), 11.02(1H, br)

Example 117

Preparation of5-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]-2-methylbenzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.0 g) obtained from Referential Example 7 was suspended in1,2-dichloroethane (20 ml), 2-thiophencarbonyl chloride (1.11 g) andpyridine (0.60 g) were added to the suspension, and the mixture wasrefluxed for 3 hours. The reaction mixture was allowed to cool, waterwas added to the mixture, extracted with chloroform. The organic layerwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure.The residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.30 g ofthe title compound as a light yellow crystal.

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.40(3H, s), 4.06-4.14(1H, m),4.44-4.53(1H, m), 4.60-4.67(1H, m), 5.47(1H, brd), 6.79-7.03(5H, m),7.30-7.32(1H, m), 7.48 (1H, brs)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Bromo-2′-methylacetophenone (0.51 g), 1N aqueous sodium hydroxide (20ml), toluene (20 ml) and tetra n-butylammonium bromide (20 mg) wereadded to2-Oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.80 g), the mixture was stirred at room temperature for 4 hours. Thereaction mixture was separated into organic layer and aqueous layer, theaqueous layer was extracted with ethyl acetate, the extract was combinedwith the former organic layer. The combined extract was successivelywashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.02 g ofthe title compound as colorless amorphous (Yield: 96%).

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.39(3H, s), 2.52(3H, s), 4.07-4.16(1H,m), 4.41-4.50(1H, m), 4.63-4.74(2H, m), 5.44(1H, d), 5.72(1H, brd),6.82-7.77(10H, m)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(l.0g) was dissolved in 4N HCl-dioxane (10 ml), the mixture was stirred at60° C. for one hour. The reaction mixture was concentrated under reducedpressure, neutralized with saturated aqueous sodium bicarbonate, andextracted with methylene chloride. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, thesolvent was evaporated under reduced pressure, to thereby obtain 0.81 gof the title compound as a light yellow crystal (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.60(2H, brs), 2.39(3H, s), 2.57(3H, s), 3.85-3.95(2H,m), 4.45-4.56(2H, m), 5.60(1H, d), 6.83-7.80(10H, m)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea

Methyl 2-methyl-5-aminobenzoate (0.37 g) was dissolved intetrahydrofuran (10 ml), triphosgene (0.22 g) was added at internaltemperature 5° C., triethylamine (0.95 g) was added thereto over 10minutes, the mixture was stirred at room temperature for 10 minutes. Asolution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.81 g) in tetrahydrofuran (10 ml) was added, the mixture was stirredat room temperature for one hour. Water was added to the reactionmixture, and extracted with chloroform. The organic layer wassuccessively washed with water and saturated brine and dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(chloroform:methanol=50:1), to thereby obtain 1.17 g ofthe title compound as light yellow amorphous (Yield: 100%).

¹H-NMR(CDCl₃) δ: 2.39(3H, s), 2.43(3H, s), 2.49(3H, s), 3.82(3H, s),4.10-4.17(1H, m), 4.55-4.65(1H, m), 4.75(1H, d), 4.97-5.07(1H, m),5.39(1H, d), 6.16(1H, brd), 6.82-7.87(13H, m)

Step 5

Preparation of5-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]-2-methylbenzoicacid

1-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea(0.70 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) andmethanol (10 ml), aqueous lithium hydroxide hydrate (0.23 g) solution(10 ml) was added, and the mixture was stirred at room temperature for 3hours. The reaction mixture was acidified with 1N HCl and extracted withchloroform. The organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography(chloroform:methanol=30:1), to thereby obtain 224 mg ofthe title compound as a white crystal.

Melting point: 192-195° C.

¹H-NMR(DMSO-d₆) δ: 2.35(3H, s), 2.39(3H, s), 2.42(3H, s), 3.85-3.92(1H,m), 4.32-4.41(1H, m), 4.63-4.73(1H, m), 5.15(1H, d), 5.39(1H, d),6.74-7.95(13H, m), 8.95(1H, brs), 12.40(1H, br)

Example 118

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

10% palladium carbon (100 mg) was added to a solution of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(500 mg) obtained from Step 1 of Referential Example 10 in ethanol (50ml), under hydrogen atmosphere the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was filtrated, thefiltrate was concentrated under reduced pressure, to thereby obtain 450mg of the title compound (Yield: 90%).

¹H-NMR(CDCl₃) δ: 1.05-2.05(19H, m), 2.27(3H, m), 3.11-3.19(1H, m),3.27-3.34(1H, m), 3.60-3.69(1H, m), 3.35-3.47(1H, m), 5.56(1H, d),6.78(1H, brs), 6.92-7.04(2H, m), 7.84(1H, brs)

Step 2

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

60% Sodium hydride (53 mg) was suspended in anhydrousN,N-dimethylformamide (5 ml), under ice-cooling2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(410 mg) was added, and the mixture was stirred at room temperature for30 minutes. Subsequently, bromomethyl-tert-butyl ketone (217 mg) wasadded to the mixture under ice-cooling, the mixture was stirred at roomtemperature for 30 minutes. Ice-water was added to the reaction mixture,extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, to thereby 517 mg of the titlecompound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.05-2.07(28H, m), 2.25(3H, s), 3.07-3.26(2H, m),3.52-3.58(1H, m), 4.08(1H, d), 4.33-4.48(1H, m), 5.16(1H, d), 5.55(1H,d), 6.77(1H, s), 6.95-7.05(2H, m)

Step 3

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

4N HCl-dioxane (7 ml) was added to a solution of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(517 mg) in ethanol (20 ml), the mixture was stirred at 50° C. for onehour. The reaction mixture was concentrated under reduced pressure,neutralized with saturated aqueous sodium bicarbonate, and extractedwith methylene chloride. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and purified by silica gelcolumn chromatography(chloroform:methanol=20:1), to thereby obtain 400mg of the title compound (Yield: 98%).

¹H-NMR(CDCl₃) δ: 1.10-2.05(21H, m), 2.27(3H, s), 3.10-3.21(2H, m),3.32-3.38(1H, m), 3.51-3.58(1H, m), 3.98(1H, d), 5.28(1H, d), 6.76(1H,s), 6.96-7.08(2H, m)

Step 4

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea

Triphosgene (122 mg) was added to a solution of ethyl 3-aminobenzoate(182 mg) in tetrahydrofuran (10 ml) under ice-cooling, triethylamine (98μl) was added thereto five times (total: 490 μl), the mixture wasstirred at room temperature for 5 minutes. A solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(393 mg) in anhydrous tetrahydrofuran (5 ml) was added to the mixtureunder ice-cooling, stirred at room temperature for 30 minutes. Ice-waterwas added to the reaction mixture, extracted with methylene chloride.The organic layer was washed with saturated brine and dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and a mixed solvent of n-hexane and ethylacetate(n-hexane:ethyl acetate=1:1) was added to the residue forcrystallization, collected by filtration, to thereby obtain 380 mg ofthe title compound.

¹H-NMR(CDCl₃) δ: 1.05-2.05(22H, m), 2.28(3H, s), 3.10-3.22(1H, m),3.34-3.42(1H, m), 3.54-3.61(1H, m), 4.25(1H, d), 4.32(2H, q),4.60-4.76(1H, m), 5.11(1H, d), 6.19(1H, d), 6.80(1H, brs), 6.98-7.10(3H,m), 7.23-7.28(1H, m), 7.52-7.65(2H, m), 7.93-7.95(1H, m)

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

1-(1-tert-Butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea(370 mg) was suspended in methanol (5 ml), aqueous lithium hydroxidemonohydrate (142 mg) solution (5 ml) was added to the suspension, andthe mixture was stirred at 50° C. for 2 hours. The reaction mixture wasfiltrated. The filtrate was acidified with 1N hydrochloric acid, andmethanol was evaporated. The mixture was extracted with ethyl acetate,the organic layer was washed with saturated brine, and dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. The residue was recrystallized from isopropyl alcohol, tothereby obtain 300 mg of the title compound (Yield: 83%).

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.10-2.05(10H, m), 2.26(3H, s),3.16-3.24(2H, m), 3.34-3.40(1H, m), 4.34-4.40(2H, m), 5.10(1H, d),6.59(1H, d), 6.83(1H, s), 7.06-7.51(5H, m), 7.98(1H, s), 9.03(1H, s),11.50(1H, br)

IR(KBr)cm⁻¹:3359, 2932, 1719, 1684, 1659

MS(FAB)m/z: 535(MH⁺)

Example 119

Preparation of3-[3-[1-(5-methylfuran-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(5-methylfuran-2-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrabydro-2H-1,5-benzodiazepine(1.0 g) obtained from Step 1 of Example 89 was dissolved intetrahydrofuran (10 ml), under argon atmosphere 60% sodium hydride (0.16g) was added, and the mixture was stirred at room temperature for 30minutes. Subsequently, a solution of 5-methyl-2-bromoacetylfuran (1.23g) in tetrahydrofuran (1 ml) was added to the mixture, stirred at roomtemperature for 30 minutes. The reaction mixture was poured intoice-water and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate,the solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography(n-hexane:ethylacetate=3:1), to thereby obtain 0.89 g of the title compound.

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.39(9H, s), 2.36(3H, s), 2.43(3H, s),3.87-3.94(1H, m), 4.19-4.36 (2H, m), 4.51-4.55(1H, m), 5.50-5.60(2H, m),6.23-6.24(1H, m), 7.10-7.29(4H, m)

Step 2

Preparation of1-(5-methylfuran-2-yl)carbonylmethyl-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(5-Methylfuran-2-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.89 g) was dissolved in 4N HCl-dioxane (10 ml), the mixture wasstirred at 40-50° C. for 20 minutes. The reaction mixture wasconcentrated under reduced pressure, the residue was neutralized withsaturated aqueous sodium bicarbonate, extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, to thereby obtain 0.71 g of title compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.03(9H, s), 1.64(2H, brs), 2.36(3H, s), 2.43(3H, s),3.63-3.77(2H, m), 4.19-4.28(2H, m), 5.65(1H, d), 6.23-6.25(1H, m),7.06-7.30(4H, m)

Step 3

Preparation of1-[1-(5-methylfuran-2yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (0.33 g) was dissolved in tetrahydrofuran (10 ml),the solution was cooled on ice, triphosgene (0.21 g) was added atinternal temperature 8° C., triethylamine (0.72 g) was added theretoover 15 minutes interval, the mixture was stirred at room temperaturefor 10 minutes. Subsequently, a solution of1-(5-methylfuran-2-yl)carbonylmethyl-2-oxo-3-amino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.71 g) in tetrahydrofuran (10 ml) was added to the mixture. Theresultant mixture was stirred at room temperature for 3 hours. Water wasadded to the reaction mixture, extracted with chloroform. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=1:1), to thereby obtain 0.82 g ofthe title compound as a light brown crystal (Yield: 78%).

¹H-NMR(CDCl₃) δ: 1.05(9H, s ), 1.35(3H, t), 2.38(3H, s), 2.39(3H, s),3.89-3.97(1H, m), 4.30-4.41(4H, m), 4.78-4.84(1H, m), 5.56(1H, d),6.07(1H, brd), 6.19-6.21(1H, m), 7.04-7.32(6H, m), 7.56-7.68(2H, m),7.90-7.92(1H, m)

Step 4

Preparation of3-[3-[1-(5-methylfuran-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(5-Methylfuran-2-yl)carbonylmethyl-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(0.80 g) was dissolved in the mixed solvent of tetrahydrofuran (10 ml)and methanol (10 ml), aqueous lithium hydroxide monohydrate (0.29 g)solution (10 ml) was added, the mixture was stirred at room temperaturefor 14 hours. The reaction mixture was concentrated under reducedpressure, the residue was weakly acidified with 1N hydrochloric acid andextracted with chloroform. The organic layer was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography(chloroform:methanol=20:1), to therebyobtain 442 mg of the title compound as a light yellow crystal.

Melting point: 224-226° C.

¹H-NMR(DMSO-d₆) δ: 0.95(9H, s), 2.38(3H, s), 2.40(3H, s), 3.60-3.67(1H,m), 4.20-4.29(1H, m), 4.47-4.51(1H, m), 4.65(1H, d), 5.37(1H, d),6.42-6.43 (1H, m), 6.70(1H, brd), 7.20-7.58 (7H, m), 7.96 (1H, s),9.04(1H, brs)

Example 120

Preparation of5-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]-2-methylbenzoicacid

Step 1

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea

Methyl 2-methyl-5-aminobenzoate (0.30 g) was dissolved intetrahydrofuran (10 ml), the solution was cooled on ice, triphosgene(0.20 g) was added at internal temperature 50° C., triethylamine (0.77g) was added thereto over 10 minutes interval, and the mixture wasstirred at room temperature for 10 minutes. Subsequently, a solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl1-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.64 g) in tetrahydrofuran (10 ml) was added to the mixture, theresultant mixture was stirred for one hour. Water was added to thereaction mixture, extracted with chloroform. The organic layer waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=3:2), to thereby obtain 0.94 g ofthe title compound as colorless powder (Yield: 100%).

¹H-NMR(CDCl₃) δ: 0.96(9H, s), 1.57(9H, s), 2.03(1H, d), 2.14(1H, d),2.38(3H, s), 2.49(3H, s), 2.50(3H, s), 3.83-3.89(4H, m), 4.54-4.88(3H,m), 5.31(1H, d), 5.98(1H, brd), 6.82-7.86(1H, m)

Step 2

Preparation of5-[3-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]-2-methylbenzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea(0.94 g) was dissolved in tetrahydrofuran (20 ml), aqueous lithiumhydroxide monohydrate (0.32 g) solution (10 ml) was added, the mixturewas stirred at 40-50° C. for 4 hours. The reaction mixture wasconcentrated under reduced pressure, the residue was weakly acidifiedwith 1N hydrochloric acid and extracted with chloroform. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and the residue was purified by silica gel columnchromatography(chloroform:methanol=30:1), to thereby obtain 0.56 g ofthe title compound as colorless powder (Yield: 61%).

¹H-NMR(DMSO-d₆) δ: 0.94(9H, s), 2.00(1H, d), 2.07(1H, d), 2.39(3H, s),2.40(3H, s), 3.41-3.47(1H, m), 7.86-4.53(2H, m), 5.18(1H, d), 5.27(1H,d), 6.66(1H, brd), 7.11-7.52(8H, m), 7.86-7.96(2H, m), 8.87(1H, s),12.67(1H, br)

Example 121

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Referential Example 10 was repeated except that2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepineobtained from Referential Example 1 was used instead of2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.41(9H, s), 1.55-2.08(6H, m), 3.23-3.37(1H, m),3.69-3.82(1H, m), 3.87-4.12(1H, m), 4.42-4.55(1H, m), 5.47-5.54(1H, m),5.62-6.01(2H, m), 6.90-6.99(2H, m), 7.08-7.22(2H, m), 7.47(1H, brs)

Step 2

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 118 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.11-2.07(19H, m), 3.15-3.27(1H, m), 3.33(1H, dd),3.68(1H, dd), 4.38-4.49(1H, m), 5.53(1H, d), 6.91-6.96(2H, m),7.11-7.16(2H, m), 7.45(1H, brs)

Step 3

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 118 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.15-2.07(28H, m), 3.13-3.24(1H, m), 3.26(1H, dd),3.61(1H, dd), 4.11(1H, d), 4.39-4.50(1H, m), 5.17(1H, d), 5.57(1H, d),6.92-7.03(2H, m), 7.12-7.20(2H, m)

Step 4

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 3 of Example 118 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.11-2.08(21H, m), 3.12-3.27(2H, m), 3.40(1H, dd),3.53-3.62(1H, m), 4.01(1H, d), 5.29(1H, d), 6.92-7.04(2H, m),7.15-7.19(2H, m)

Step 5

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea

Step 4 of Example 118 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.08-2.09(22H, m), 3.15-3.26(1H, m), 3.41(1H, dd),3.65(1H, dd), 4.29(1H, d), 4.33(2H, t), 4.67-4.79(1H, m), 5.11(1H, d),6.17(1H, d), 6.97-7.07(3H, m), 7.17-7.30(3H, m), 7.53-7.56(1H, m),7.62-7.66(1H, m), 7.92-7.94(1H, m)

Step 6

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 5 of Example 118 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylphenyl)urea, to thereby obtain the title compound.

Melting point: 250-252° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.05-2.08(19H, m), 3.16-3.49(3H, m), 4.33-4.40(1H,m), 4.39(1H, d), 5.12(1H, d), 6.62(1H, d), 6.98-7.14(2H, m),7.23-7.36(3H, m), 7.44-7.52(2H, m), 7.99(1H, brs), 9.06(1H, brs),11.50(1H, br)

IR(KBr)cm⁻¹:3360, 1721, 1686, 1655

MS(FAB)m/z: 521(MH⁺)

The structure of these compounds obtained from Example 89-121 was shownin Table 13-17.

TABLE 13

Example R₁ R₂ R₃ R_(p) n 89 8-CH₃

1 90 8-CH₃O

1 91 8-CH₃

1 92 8-CH₃

1 93 8-CH₃

1 94 8-CH₃

1 95 8-CH₃

1

TABLE 14

Example R₁ R₂ R₃ R_(p) n  96 (*) 8-CH₃

1  97 (*) 8-CH₃

1  98 8-CH₃

1  99 8-CH₃

1 100 8-CH₃

1 101 H

1 102 8-CH₃

1 (*): optically active compound

TABLE 15

Example R₁ R₂ R₃ R_(p) n 103 8-CH₃

1 104 8-CH₃

1 105 8-CH₃

1 106 8-CH₃

1 107 8-CH₃

1 108 8-CH₃

1 109 8-CH₃

1

TABLE 16

Example R₁ R₂ R₃ R_(p) n 110 8-CH₃

1 111 8-CH₃

1 112 8-CH₃

1 113 8-CH₃

1 114 8-CH₃

1 115 8-CH₃

1 116 8-CH₃

1

TABLE 17

Example R₁ R₂ R₃ R_(p) n 117 8-CH₃

1 118 8-CH₃

1 119 8-CH₃

1 120 8-CH₃

1 121 H

1

Example 122

Preparation of3-[3-[1-(2-thenoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2-thenoylmethyl)-2-oxo-3-(N-tert-butoxycarbonyl)amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-(N-tert-butoxycarbonyl)amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.40 g) was dissolved in N,N-dimethylformamide (20 ml), the solutionwas cooled to internal temperature 5° C., 60% sodium hydride (0.29 g)was added under argon atmosphere, the mixture was stirred at internaltemperature 5° C. for 30 minutes. Subsequently, 2-bromoacetylthiophene(1.47 g) was added to the mixture, stirred at internal temperature 5° C.for one hour and 30 minutes. The reaction mixture was poured intoice-water and extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography(ethylacetate:n-hexane=1:2), to thereby obtain 2.25 g of the title compound(Yield: 71.3%).

Melting point: 148-150° C.

¹H-NMR(DMSO-d₆) δ: 1.35(9H, s), 2.37(3H, s), 3.65-3.71(1H, m),4.34-4.42(1H, m), 4.51(1H, q), 5.16(1H, d), 5.45(1H, d), 6.69(1H, brs),6.87(1H, t-like), 7.02(2H, s), 7.26-7.30(1H, m), 7.36(1H, s), 7.42(1H,d), 7.63-7.65(1H, m), 8.06(1H, dd), 8.14(1H, d)

Step 2

Preparation of1-(2-thenoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Thenoylmethyl)-2-oxo-3-(N-tert-butoxycarbonyl)amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) was dissolved in 4N HCl-dioxane (20 ml), the mixture wasstirred at 60° C. for 30 minutes. The reaction mixture was concentratedunder reduced pressure, saturated aqueous sodium bicarbonate and ethylacetate were added to the residue, and extracted. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, the residuewas purified by silica gel columnchromatography(methanol:chloroform=1:20), to thereby obtain 1.36 g oftitle compound as amorphous (Yield: 84.1%).

¹H-NMR(CDCl₃) δ: 2.39(3H, s), 3.71-3.94(2H, m), 4.44(1H, m), 4.42(1H,d), 5.65(1H, d), 6.84-6.87(1H, m), 7.02-7.05(3H, m), 7.16-7.19(2H, m),7.32(11H, dd), 7.72(1H, dd), 7.85(1H, dd)

Step 3

Preparation of1-[1-(2-thenoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (0.54 g) was dissolved in tetrahydrofuran (15 ml),the solution was cooled to internal temperature 5-8° C. Triphosgene(0.35 g) was added, the mixture was stirred for 5 minutes. Subsequently,triethylamine (1.20 g) was added to the mixture over 15 minutesinterval, stirred at room temperature for 10 minutes, and a solution of1-(2-thenoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.26 g) in tetrahydrofuran (15 ml) was added, stirred for one hour.Water and chloroform were added to the reaction mixture, and extracted.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, crystals so precipitated were collected by filtration withether, to thereby obtain 1.46 g of the title compound (Yield: 79.8%).

Melting point: 244.5° C.

¹H-NMR(DMSO-d₆) δ: 1.32(3H, t), 2.40(3H, s), 3.85-3.92(1H, m),4.25-4.37(3H, m), 4.62-4.69(1H, m), 5.11(1H, d), 5.54(1H, d),6.72-6.75(2H, m), 6.85(1H, t), 7.04-7.14(2H, m), 7.24-7.35(3H, m),7.49-7.51(2H, m), 7.60(1H, d), 8.01-8.04(2H, m), 8.12(1H, d), 9.04(1H,s)

Step 4

Preparation of3-[3-[1-(2-thenoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Thenoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea(1.3 g) was suspended in tetrahydrofuran (30 ml), aqueous lithiumhydroxide monohydrate (0.44 g) solution (15 ml) was added, the mixturewas stirred at 40-50° C. for 6 hours. The solvent was concentrated underreduced pressure, 1N hydrochloric acid and chloroform were added to theresidue, crystals so precipitated were collected by filtration, washedwith a mixed solvent(chloroform:methanol=10:1), and filtrated by meansof suction, to thereby obtain 102 mg of the title compound.

Melting point:over 290° C.

¹H-NMR(DMSO-d₆) δ: 2.39(3H, s), 3.84-3.91(1H, m), 4.34(1H, t),4.62-4.72(1H, m), 5.12(1H, d), 5.54(1H, d), 6.71-6.78(2H, m),6.84-6.88(1H, m), 7.07-7.15 (2H, m), 7.25-7.33(3H, m), 7.46-7.53(2H, m),7.61(1H, d), 7.99-8.04(2H, m), 8.12(1H, d), 9.02(1H, s)

MS(FAB)m/z: 589(MH⁺)

IR(KBr)cm⁻¹:3354, 1672, 1649, 1593, 1541, 1508, 1417, 1244

Example 123

Preparation of3-[3-[1-(2-thenoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2-thenoylmethyl)-2-oxo-3-(N-tert-butoxycarbonyl)amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-(N-tert-butoxycarbonyl)amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.00 g) was dissolved in N,N-dimethylformamide (20 ml), the solutionwas cooled to internal temperature 5° C. Under argon atmosphere 60%sodium hydride (0.28 g) was added, the mixture was stirred at internaltemperature 5° C. for 30 minutes. Subsequently, 2-bromoacetylthiophene(1.42 g) was added to the mixture, the resultant mixture was stirred atinternal temperature 5° C. for 1 hour and 30 minutes. The reactionmixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(ethyl acetate:n-hexane=1:2), to thereby obtain 1.49 g ofthe title compound.

Melting point: 166-168° C.

¹H-NMR(CDCl₃) δ: 1.16-2.05(19H, m), 3.17-3.21(1H, m), 3.26-3.33(1H, m),3.57-3.65(1H, m), 4.44-4.51(1H, m), 4.68(1H, d), 5.41(1H, d), 5.57(1H,d), 6.98-7.04(1H, m), 7.12-7.18(4H, m), 7.69(1H, dd), 7.84(1H, dd)

Step 2

Preparation of1-(2-thenoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-Thenoylmethyl)-2-oxo-3-(N-tert-butoxycarbonyl)amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.30 g) was dissolved in 4N HCl-dioxane (15 ml), the mixture wasstirred at 60° C. for 30 minutes. The reaction mixture was concentratedunder reduced pressure, methylene chloride and saturated aqueous sodiumbicarbonate were added and extracted. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, the residue was purifiedby silica gel column chromatography(methanol:chloroform=1:20), tothereby obtain 0.99 g of title compound as amorphous (Yield: 94.3%).

¹H-NMR(CDCl₃) δ: 1.17-2.00(10H, m), 3.17-3.73(4H, m), 4.58(1H, d),5.54(1H, d), 6.99-7.05(1H, m), 7.14-7.19(4H, m), 7.70(1H, dd), 7.86(1H,dd)

Step 3

Preparation of1-[1-(2-thenoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (0.48 g) was dissolved in tetrahydrofuran (25 ml),the solution was cooled to internal temperature 5-8° C. Triphosgene(0.32 g) was added, and the mixture was stirred for 5 minutes.Subsequently, triethylamine (1.08 g) was added over 15 minutes interval.The resultant mixture was stirred at room temperature for 10 minutes,asolution of1-(2-thenoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.99 g) in tetrahydrofuran (15 ml) was added and stirred for one hour.Water and chloroform were added to the reaction mixture and extracted.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, a mixed solvent of methylene chloride and ether (1:1) wasadded to crystals so precipitated for trituration, collected byfiltration, to thereby obtain 1.07 g of the title compound.

Melting point: 219-220° C.

¹H-NMR(DMSO-d₆) δ: 1.22-1.99(13H, m), 3.25-3.45(3H, m), 4.28(2H, q),4.41-4.46(1H, m), 4.95(1H, d), 5.48(1H, d), 6.61(1H, d), 7.11-7.19(2H,m), 7.28-7.38(4H, m), 7.50(2H, d-like), 8.05(1H, t), 8.08(1H, dd),9.09(1H, s)

Step 4

Preparation of3-[3-[1-(2-thenoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Thenoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea(0.70 g) was dissolved in tetrahydrofuran (19 ml), aqueous lithiumhydroxide monohydrate (0.26 g) solution (15 ml) and methanol (7 ml) wereadded, the mixture was stirred at 40-50° C. for one hours. The reactionmixture was concentrated under reduced pressure, 1N hydrochloric acidand chloroform were added to the residue, and extracted. The organiclayer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, a mixed solvent of methylene chloride and ether (1:1) wasadded to powder so precipitated, and collected by filtration,to therebyobtain 0.61 g of the title compound (Yield: 92.4%).

¹H-NMR(DMSO-d₆) δ: 1.18-1.98(10H, m), 3.22-3. 46(3H, m), 4.39-4.82(1H,m), 4.95(1H, d), 5.48(1H, d), 6.63(1H, d), 7.09-7.20(2H, m), 7.28-7.35(4H, m), 7.46-7.52 (2H, m), 7.99 (1H, t), 8.08(1H, dd), 8.15(1H, dd),9.05(1H, s)

MS (FAB) m/z: 547 (MH⁺)

IR(KBr)cm⁻¹:3360, 2932, 1686, 1551, 1496, 1415, 1238

Example 124

Preparation of3-[3-[1-(pyrrolidin-1-ylcarbonylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureidolbenzoicacid

Step 1

Preparation of1-(pyrrolidin-1-ylcarbonylmethyl)-2-oxo-3-(N-tert-butoxycarbonyl)amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-(N-tert-butoxycarbonyl)amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.75 g) was dissolved in N,N-dimethylformamide (20 ml), the solutionwas cooled to internal temperature 50° C. Under argon atmosphere 60%sodium hydride (0.28 g) was added,stirred at internal temperature 5° C.for 30 minutes. Subsequently, 1-bromoacetylpyrrolidine (1.33 g) wasadded to the mixture, stirred at internal temperature 50° C. for 1 hourand 30 minutes. The reaction mixture was poured into ice-water andextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure,and the residue waspurified by silica gel column chromatography(ethylacetate:n-hexane=1:2), to thereby obtain 1.25 g of the title compound(Yield: 54.5%).

Melting point: 159-161° C.

¹H-NMR(CDCl₃) δ: 1.18-1.41(14H, m), 1.54-2.05(9H, m), 3.14-3.30(2H, m),3.38-3.66(5H, m), 3.88(1H, d), 4.39-4.48(1H, m), 4.92(1H, d), 5.61(1H,d), 6.98-7.04(1H, m), 7.12-7.17(2H, m), 7.37(1H, d)

Step 2

Preparation of1-(pyrrolidin-1-ylcarbonylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(Pyrrolidin-1-ylcarbonylmethyl)-2-oxo-3-(N-tert-butoxycarbonyl)amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin(1.10 g) was dissolved in 4N HCl-dioxane (15 ml), the mixture wasstirred at 60° C. for 30 minutes. After the reaction mixture wasconcentrated under reduced pressure, methylene chloride and saturatedaqueous sodium bicarbonate was added to the residue, extracted. Theorganic layer was washed with water and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(methanol:chloroform=1:20), to thereby obtain 1.10 g ofthe title compound (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.18-1.37(5H, m), 1.56-1.68(3H, m), 1.84-2.05(6H, m),3.14-3.26(2H, m), 3.36-3.67(6H, m), 3.80(1H, d), 5.17(1H, d),7.00-7.06(1H, m), 7.16-7.18(2H, m), 7.39(1H, d-like)

Step 3

Preparation of1-[1-(pyrrolidin-1-ylcarbonylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (0.43 g) was dissolved in tetrahydrofuran (25 ml),the solution was cooled to internal temperature 5-8° C. Triphosgene(0.28 g) was added to the solution, and stirred for 5 minutes.Subsequently, triethylamine (0.95 g) was added dropwise over 15 minutesinterval. The mixture was stirred at room temperature for 10 minutes, asolution of1-(pyrrolidin-1-ylcarbonylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(0.87 g) in tetrahydrofuran (15 ml) was added to the mixture, theresultant mixture was stirred for one hour. Water and chloroform wereadded to the reaction mixture and extracted. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, ether was added tocrystals so precipitated for trituration, collected by filtration, tothereby obtain 1.20 g of the title compound (Yield: 91.3%).

Melting point: 240-243° C.

¹H-NMR(CDCl₃) δ: 0.99-1.28(5H, m), 1.34(3H, t), 1.47-1.55(3H, m),1.77-2.05(6H, m), 3.18-3.22(1H, m), 3.42-3.64(6H, m), 4.17(1H, d),4.32(2H, q), 4.68-4.77(1H, m), 4.79(1H, d), 6.21(1H, d), 7.00-7.06(1H,m), 7.18-7.30(4H, m), 7.60-7.68(2H, m), 7.72(1H, s), 7.98(1H, t)

Step 4

Preparation of3-[3-[1-(pyrrolidin-1-ylcarbonylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(Pyrrolidin-1-ylcarbonylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(4-ethoxycarbonylphenyl)ureawas suspended in tetrahydrofuran (20 ml), aqueous lithium hydroxide(0.37 g) solution (10 ml) and methanol (20 ml) were added, the mixturewas stirred at 40-50° C. for one hour. 1N hydrochloric acid andchloroform were added and extracted. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, isopropyl ether wasadded to crystals so precipitated for trituration, collected byfiltration, to thereby obtain 0.81 g of the title compound (Yield:85.1%).

Melting point: 223° C. (forming)

¹H-NMR(DMSO-d₆) δ: 1.17-1.35(4H, m), 1.51-1.60(4H, m), 1.76-1.96(6H, m),3.20-3.51(7H, m), 4.08(1H, d), 4.32-4.42(1H, m), 4.83(1H, d), 6.58(1H,d), 7.08-7.14 (1H, m), 7.23-7.35(4H, m), 7.46-7.52 (2H, m), 7.98(1H, t),8.32(1H, s)

MS (FAB) m/z: 534(MH⁺)

IR(KBr)cm⁻¹:3324, 2930, 1686, 1660, 1595, 1556, 1496, 1448, 1219

Example 125

Preparation of(R)-(−)-2-methyl-2-[3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenoxy]propionicacid

Step 1

Preparation of2-methyl-2-[3-(N-tert-butoxycarbonyl)aminophenoxy]propionic acid

3-(N-tert-Butoxycarbonyl)aminophenol (683 mg) was suspended in asolution of sodium hydroxide (1.70 g) in acetone (20 ml) underice-cooling, chloroform (0.79 ml) was added, and then refluxed one hour.After the reaction mixture was allowed to cool, water and chloroformwere added, extracted. The aqueous layer was acidified with 1Nhydrochloric acid, and extracted with ethyl acetate. The ethyl acetatelayer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, to thereby obtain 675 mg of the title compound as pale yellowoil (Yield: 70.2%).

¹H-NMR(CDCl₃) δ: 1.51(9H, s), 1.61(6H, s), 6.61(1H, ddd), 7.01(1H,d-like), 7.08(1H, brs), 7.17(1H, t)

Step 2

Preparation of benzyl2-methyl-2-[3-(N-tert-butoxycarbonyl)aminophenoxy]propionate

2-Methyl-2-[3-(N-tert-butoxycarbonyl)aminophenoxy]propionic acid (675mg) was dissolved in N,N-dimethylformamide (10 ml), benzyl bromide (0.30ml) and potassium carbonate (633 mg) were added, and then stirred forone hour and 30 minutes at internal temperature 70° C. The reactionmixture was poured into ice-water and extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonate,water and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, to thereby obtain 882mg of the title compound as pale yellow oil (Yield: 100%).

¹H-NMR(CDCl₃) δ: 1.51(9H, s), 1.62(6H, s), 5.22(2H, s), 6.19(1H, brs),6.42-6.46(1H, m), 6.71(1H, m), 7.00-7.10(2H, m), 7.33(5H, s)

Step 3

Preparation of benzyl 2-methyl-2-(3-aminophenoxy)propionate

Benzyl 2-methyl-2-[3-(N-tert-butoxycarbonyl)aminophenoxy]propionate (882mg) was dissolved in 4N HCl-dioxane (5.7 ml) and then stirred for 30minutes at 50° C. After the solvent was evaporated under reducedpressure, methylene chloride and saturated aqueous sodium bicarbonatewere added to the residue, and extracted. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, the residue waspurified by silica gel column chromatography(chloroform), to therebyobtain 270 mg of the title compound as oil.

¹H-NMR(CDCl₃) δ: 1.60(6H, s), 3.50(2H, brs), 5.21(2H, s), 6.08(1H, t),6.17(1H, ddd), 6.29(1H, ddd), 6.93(1H, t), 7.32(5H, s)

Step 4

Preparation of(R)-(−)-2-methyl-2-[3-[1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenoxy]propionicacid benzyl ester

Benzyl 2-methyl-2-(3-aminophenoxy)propionate (200 mg) was dissolved intetrahydrofuran (5 ml), the solution was cooled to internal temperature5-8° C. Triphosgene (77 mg) was added, stirred for 5 minutes.Subsequently, triethylamine (0.36 g) was added every 5 minutes afterdivided into two portions. The mixture was stirred at room temperaturefor 10 minutes, a solution of(R)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(230 mg) in tetrahydrofuran (5 ml) was added to the mixture, stirred forone hour. Water and chloroform were added to the reaction mixture, andextracted. The organic layer was washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the residue was purified by silica gel columnchromatography(chloroform), to thereby obtain 310 mg of the titlecompound as pale yellow oil (Yield: 72.4%).

¹H-NMR(CDCl₃) δ: 1.24(9H, s), 1.57(6H, s), 1.11-1.85(9H, m), 2.00(1H,m), 3.20(1H, m), 3.26-3.31(1H, m), 3.69-3.73(1H, m), 4.18(1H, d),4.64-4.68(1H, m), 5.14(1H, d), 5.20(2H, s), 5.81(1H, d), 6.16(1H, s),6.42-6.46(1H, m), 6.66(1H, t), 6.90-7.06(4H, m), 7.17-7.19(2H, m),7.32-7.35(5H, m)

[α] D²⁵ (C=0.375, CHCl₃): −64.8°

Step 5

Preparation of(R)-(−)-2-methyl-2-[3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenoxy]propionicacid

(R)-(−)-2-Methyl-2-[3-[1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenoxy]propionicacid benzyl ester (210 mg) was dissolved in ethanol (5 ml), 10%palladium carbon (21 mg) was added, and the mixture was stirred for 2hours at room temperature under hydrogen atmosphere. The reactionmixture was filtrated through a pad of Celite, the filtrate wasconcentrated under reduced pressure. n-Hexane was added to the residue,collected by filtration,to thereby obtain 170 mg of the title compound(97.2%).

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.46(6H, s), 1.11-1.99(10H, m),3.21-3.25(3H, m), 4.35-4.42(2H, m), 5.13(1H, d), 6.33-6.37(1H, m),6.54(1H, d), 6.81(1H, m), 6.99-7.10(4H, m), 7.25-7.27(2H, m), 8.82(1H,s), 12.90(1H, brs)

MS(FAB)m/z: 579(MH⁻)

IR(KBr)cm⁻¹:3370, 2934, 1724, 1647, 1597, 1551, 1496, 1153

[α] D²⁵ (C=0.8, CHCl₃): −60.1°

Example 126

Preparation of(−)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of(−)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(7.98 g) was dissolved in ethanol (100 ml), (+)-debenzoyl tartaric acid(3.96 g) was added under reflux, and then refluxed for 5 minutes,allowed to cool overnight,crystals so precipitated were collected byfiltration, to thereby obtain (+)-dibenzoyl tartaric acid salt.

Melting point: 184-185° C.

The obtained (+)-dibenzoyl tartaric acid salt was suspended in saturatedaqueous sodium bicarbonate and extracted with chloroform. The organiclayer was washed with water and saturated brine, and dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, to thereby obtain 2.23 g of the title compound as colorlessamorphous.

Optical purity: 98%ee (the ee value was determined by High PerformanceLiquid Chromatography)

[α] D²⁵ (C=1.00, CH₂Cl₂): −39.1°

Step 2

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

Tert-butyl 3-aminobenzoate (1.09 g) was dissolved in tetrahydrofuran (20ml), triphosgene (0.61 g) was added to a solution under ice-cooling.Subsequently, under ice-cooling triethylamine (2.12 g) was addeddropwise, and the mixture was stirred at room temperature for one hour.A solution of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.23 g) in tetrahydrofuran (20 ml) was added to the mixture, stirred atroom temperature for one hour. The reaction mixture was concentratedunder reduced pressure, 1N hydrochloric acid was added to the residueand extracted with chloroform. The organic layer was washed with water,saturated aqueous sodium bicarbonate and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=1:1), to thereby obtain 3.35 g ofthe title compound as colorless amorphous (Yield: 100%).

Step 3

Preparation of(−)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea(3.35 g) was dissolved in trifluoroacetic acid (30 ml), and then stirredfor one hour at room temperature. The reaction mixture was concentratedunder reduced pressure, hexane was added to the residue for trituration,and collected by filtration, to thereby obtain 3.04 g of the titlecompound as colorless powder (Yield: 99%).

Optical purity: 97.8%ee (the ee value was determined by High PerformanceLiquid Chromatography)

[α] D (C=1.017, CHCl₃): −59.6°

Example 127

Preparation of various salts of(−)-3-[3-(l-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

(1) Preparation of (+)-phenethylamine salt

(−)-3-[3-(1-tert-Butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid (300 mg) was dissolved in methanol (3 ml), (+)-α-phenethylamine (71mg) was added, the mixture was refluxed, and the reaction mixture wasallowed to cool under agitation. Crystals so precipitated were collectedby filtration and dried under reduced pressure, to thereby obtain 86 mgof the title salt as a colorless crystal.

Melting point: 176-177° C.

¹H-NMR(DMSO-d₆) δ: 1.17(9H, s), 1.34(3H, d), 3.46(3H, br), 3.98-4.04(1H,m), 4.14(1H, q), 4.56-4.61(1H, m), 4.76(1H, d), 5.11(1H, d),6.79-6.87(4H, m), 7.13-7.54(15H, m), 7.90(1H, s), 9.15(1H, s)

(2) Preparation of benzylamine salt

Free compound (100 mg) was dissolved in acetonitrile (1 ml), benzylamine(21 mg) was added, and the mixture was refluxed. The reaction mixturewas allowed to cool under agitation, crystals so precipitated werecollected by filtration and dried under reduced pressure, to therebyobtain 91 mg of benzylamine salt as a colorless crystal.

Melting point: 161-1630° C.

(3) Preparation of 4-methylbenzylamine salt

Free compound (100 mg) was dissolved in acetonitrile (1 ml),4-methylbenzyl amine (24 mg) was added, the mixture was refluxed. Thereaction mixture was allowed to cool, crystals so precipitated werecollected by filtration and dried, to thereby obtain 92 mg of the titlesalt as a colorless crystal.

Melting point: 172-174° C.

Example 128

Preparation of(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid (−)-α-phenethylamine salt

Free compound (300 mg) was dissolved in acetonitrile (2 ml),(−)-α-phenethylamine (69 mg) was added under heating and refluxed for 5minutes. The reaction mixture was allowed to cool, crystals soprecipitated were collected by filtration, and dried, to thereby obtain327 mg of the title compound as a colorless crystal.

Melting point: 169-171° C.

Example 129

Preparation of(−)-3-[3-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid (+)-α-phenethylamine salt

Free compound (10 mg) was dissolved in acetonitrile (1 ml),(+)-α-phenethylamine was added, and stirred at room temperature.Crystals so precipitated were collected by filtration and dried, tothereby obtain 8.7 mg of the title compound as a colorless crystal.

Melting point: 178-181° C.

Example 130

Preparation of(+)-3-[3-[1-(2-thenoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid (+)-α-phenethylamine salt

Free compound (10 mg) was dissolved in acetonitrile (1 ml),(+)-α-phenethylamine (2 mg) was added, and stirred at room temperature.Crystals so precipitated were collected by filtration and dried, tothereby obtain 8.0 mg of the title compound as a colorless crystal.

Melting point: 156-160° C.

Example 131

Preparation of3-[3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yllureidolbenzoicacid

Step 1

Preparation of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Under argon atmosphere2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) was added to a suspension of 60% sodium hydride (222 mg) inanhydrous tetrahydrofuran (30 ml), and the mixture was stirred at roomtemperature for 30 minutes. Subsequently,2-bromo-(N-methyl-N-phenyl)acetamide (951 mg) was added, and the mixturewas stirred at room temperature for one hour. The reaction mixture wasconcentrated under reduced pressure, ice-water (50 ml) was added andextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain1.13 g of the title compound (Yield: 80.2%).

¹H-NMR(CDCl₃) δ: 1.03-1.68(8H, m), 1.38(9H, s), 1.74-1.85(1H, m),1.94-2.09(1H, m), 3.03-3.16(1H, m), 3.21(1H, dd), 3.35(3H, s),3.55-3.70(2H, m), 4.42(1H, dt), 4.66(1H, d), 5.61(1H, d), 6.96-7.05(1H,m), 7.07-7.19(2H, m), 7.26-7.48(6H, m)

Step 2

Preparation of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

1-(N-Methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.13 g) was dissolved in ethanol (20 ml), 4N HCl-dioxane (10 ml) wasadded, and the mixture was stirred at 50° C. for 30 minutes. Thereaction mixture was concentrated under reduced pressure, saturatedaqueous sodium bicarbonate was added and extracted with methylenechloride. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure, to thereby obtain 907mg of the titled compound.

¹H-NMR(CDCl₃) δ: 1.03-1.40(4H, m), 1.45-1.70(6H, m), 1.73-1.85(1H, m),1.93-2.05(1H, m), 3.03-3.22(2H, m), 3.33-3.43(1H, m), 3.36(3H, s),3.50-3.62(2H, m), 4.76(1H, d), 6.98-7.07(1H, m), 7.10-7.17(2H, m),7.25-7.49(6H, m)

Step 3

Preparation of1-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Ethyl 3-aminobenzoate (406 mg) was dissolved in anhydroustetrahydrofuran (20 ml), triphosgene (243 mg) was added underice-cooling, triethylamine (0.21 ml) was added thereto five times every3 minutes, and the mixture was stirred for one hour under ice-cooling. Asolution of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(907 mg) in anhydrous tetrahydrofuran (20 ml) was added, the mixture wasallowed to come to room temperature, and stirred for one hour. Thereaction mixture was concentrated under reduced pressure, water (50 ml)was added and extracted with methylene chloride. The organic layer wasdried over anhydrous sodium sulfate, the solvent was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=4:3), and isopropyl ether wasadded to the residue for trituration, collected by filtration, tothereby obtain 1.10 g of the titled compound (Yield: 82.5%).

¹H-NMR(DMSO-d₆, 80° C.) δ: 1.03-1.35(4H, m), 1.30(3H, t), 1.40-1.60(4H,m), 1.65-1.77(1H, m), 1.88-2.00(1H, m), 3.10-3.45(6H, m), 3.75-3.90(1H,m), 4.22-4.55(2H, m), 4.28(2H, q), 6.58(1H, d), 7.09-7.18(1H, m),7.22-7.55(11H, m), 8.03(1H, t), 9.09(1H, s)

Step 4

Preparation of3-[3-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

1-[1-(N-Methyl-N-phenylcarbamoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(1.0 g) was dissolved in a mixed solvent of methanol (50 ml) andtetrahydrofuran (25 ml), aqueous lithium hydroxide monohydrate (350 mg)solution (25 ml) was added, and the mixture was refluxed for 30 minutes.The reaction mixture was concentrated under reduced pressure, theresidue was acidified with 1N hydrochloric acid, extracted withmethylene chloride. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, the solvent was evaporated underreduced pressure, and isopropyl ether was added to the residue fortrituration, collected by filtration, to thereby obtain 904 mg of thetitled compound (Yield: 95.0%).

Melting point: 244-248° C. (decomposition)

¹H-NMR(DMSO-d₆, 80° C.) δ: 1.05-1.79(9H, m), 1.87-1.98(1H, m),3.10-3.25(2H, m), 3.42(1H, dd), 3.87(1H, d), 4.36(1H, dt), 4.55(1H, d),6.46(1H, d), 7.05-7.15(1H, m), 7.20-7.54(12H, m), 7.95(1H, t), 8.86(1H,s)

MS(FAB)m/z: 570(MH⁺) 133(base)

IR(KBr)cm⁻¹:3325, 2932, 1686, 1653, 1595, 1559, 1497, 1242, 758

Example 132

Preparation of3-[3-[1-(N-tert-butyl)carbamoylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-(N-tert-butyl)carbamoylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) was suspended in toluene (25 ml), N-tert-butyl-2-bromoacetamide(1.14 g), 1N aqueous sodium hydroxide (15 ml) and tetra n-butylammoniumbromide (90 mg) were added thereto, and the mixture was stirred at roomtemperature overnight. Water and ethyl acetate were added to thereaction mixture, separated. The aqueous layer was extracted with ethylacetate, the ethyl acetate extract was combined with the former organiclayer, and the combined extract was washed with saturated brine, driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, ether was added to the residue for trituration, collected byfiltration, to thereby obtain 1.09 g of the title compound (Yield:83.0%).

¹H-NMR(CDCl₃) δ: 1.10-1.90(9H, m), 1.31(9H, s), 1.40(9H, s),2.00-2.10(1H, m), 3.10-3.22(1H, m), 3.29(1H, dd), 3.48-3.57(1H, m),4.20(1H, d), 4.31-4.42(1H, m), 4.45(1H, d), 5.41(1H, d), 6.11(1H, brs),7.05-7.13(1H, m), 7.17-7.25(3H, m)

Step 2

Preparation of1-(N-tert-butyl)carbamoylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 131 was repeated except that1-(N-tert-butyl)carbamoylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.10-1.90(11H, m), 1.30(9H, s), 2.01-2.13(1H, m),3.08-3.21(1H, m), 3.24(1H, dd), 3.38(1H, dd), 3.51(1H, dd), 4.30(1H, d),4.39(1H, d), 6.10(1H, brs), 7.05-7.13(1H, m), 7.17-7.30(3H, m)

Step 3

Preparation of1-[1-(N-tert-butyl)carbamoylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea

Step 3 of Example 131 was repeated except that1-(N-tert-butyl)carbamoylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.10-1.80(21H, m), 1.88-2.00(1H, m), 3.17-3.44(3H,m), 3.75(1H, d), 4.28(2H, q), 4.22-4.39(1H, m), 4.64(1H, d), 6.64(1H,d), 7.10-7.18(1H, m), 7.23-7.38(4H, m), 7.46-7.56(3H, m), 8.04(1H, t),9.12(1H, s)

Step 4

Preparation of3-[3-[1-(N-tert-butyl)carbamoylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 131 was repeated except that1-[1-(N-tert-butyl)carbamoylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)ureawas used instead of1-[1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 230-234° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.10-1.80(18H, m), 1.88-2.00(1H, m), 3.15-3.45(3H,m), 3.75(1H, d), 4.27-4.40(1H, m), 4.63(1H, d), 6.69(1H, d),7.08-7.18(1H, m), 7.21-7.35(4H, m), 7.42-7.58(3H, m), 7.99(1H, t),9.20(1H, s), 12.60-13.00(1H, br)

MS(FAB)m/z: 536(MH⁺)

IR(KBr)cm⁻¹:3316,2932, 1686, 1655, 1551, 756

Example 133

Preparation of3-[3-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 131 was repeated except that3-bromoacetyl-2,5-dimethylthiophene was used instead of2-bromo-(N-methyl-N-phenyl)acetamide, to thereby obtain the titlecompound.

¹H-NMR(CDCl₃) δ: 1.17-1.88(9H, m), 1.39(9H, s), 1.96-2.08(1H, m),2.41(3H, s), 2.71(3H, s), 3.12-3.25(1H, m), 3.29(1H, dd), 3.57-3.70(1H,m), 4.39(1H, d), 4.45-4.54(1H, m), 5.37(1H, d), 5.56-5.64(1H, m),6.94-7.18(5H, m)

Step 2

Preparation of1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 131 was repeated except that1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.10-2.15(12H, m), 2.41(3H, s), 2.72(3H, s),3.12-3.33(2H, m), 3.39-3.47(1H, m), 3.61-3.72(1H, m), 4.32(1H, d),5.48(1H, d), 6.92-7.22(5H, m)

Step 3

Preparation of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

Step 3 of Example 131 was repeated except that1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that tert-butyl 3-aminobenzoate was used instead of ethyl3-aminobenzoate, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.02-1.86(18H, m), 1.94-2.06(1H, m), 2.35(3H, s),2.65(3H, s), 3.11-3.23(1H, m), 3.38(1H, dd), 3.67(1H, dd), 4.49(1H, d),4.78(1H, dt), 5.38(1H, d), 6.23(1H, d), 6.93-7.37(7H, m), 7.53-7.62(1H,m), 7.65-7.72(1H, m), 7.80(1H, dt)

Step 4

Preparation of3-[3-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Trifluoroacetic acid (5 ml) was added to a solution of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea(450 mg) in anhydrous methylene chloride (10 ml), and the mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, ethanol was added to the residue,crystals were collected by filtration, to thereby obtain 202 mg of thetitle compound.

Melting point: : 226-229° C. (decomposition)

¹H-NMR(DMSO-d₆) δ:

1.10-1.83(9H, m), 1.94-2.05(1H, m), 2.39(3H, s), 2.62(3H, s),3.15-3.38(2H, m), 3.44(1H, dd), 4.44(1H, dt), 4.67(1H, d), 5.32(1H, d),6.61(1H, d), 7.07-7.12(2H, m), 7.22-7.37(4H, m), 7.49(2H, tq), 7.99(1H,t), 9.04(1H, s), 12.70-13.00(1H, br)

MS(FAB)m/z: 575(MH⁺), 154(base)

IR(KBr)cm⁻¹:3337, 2934, 1692, 1670, 1661, 1557, 1238, 760

Example 134

Preparation of2-methoxy-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methoxycarbonyl-4-methoxyphenyl)urea

Step 3 of Example 131 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that methyl 5-amino-2-methoxybenzoate was used instead of ethyl3-aminobenzoate, to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.10-1.82(9H, m), 1.93-2.05(1H, m),3.13-3.50(3H, m), 3.74(3H, s), 3.75(3H, s), 4.30-4.45(2H, m), 5.11(1H,d), 6.49(1H, d), 6.97-7.13(3H, m), 7.20-7.30(2H, m), 7.38(1H, dd),7.69(1H, d), 8.79(1H, s)

Step 2

Preparation of2-methoxy-5-[3-[1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 131 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methoxycarbonyl-4-methoxyphenyl)ureawas used instead of1-(1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 207˜209° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.10˜1.82(9H, m), 1.93˜2.05(1H, m),3.15˜3.45(3H, m), 3.74(3H, s), 4.30˜4.45(2H, m), 5.12(1H, d), 6.48(1H,d), 6.95˜7.03(2H, m), 7.05˜7.13(1H, m), 7.20˜7.30(2H, m), 7.39(1H, dd),7.63(1H, d), 8.76 (1H, s), 12.30˜12.70(1H, br)

MS(FAB)m/z: 551(MH⁺), 133(base)

IR(KBr)cm⁻¹:3386, 3340, 3289, 2934, 1742, 1686, 1661, 1553, 1497, 1221

Example 135

Preparation of3-[3-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2-thenoyl)methyl-2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 109 was repeated except that 2-bromoacetyl thiophenewas used instead of 2-bromo-2′-methylacetophenone, to thereby obtain thetitle compound.

¹H-NMR(CDCl₃) δ: 0.96(9H, s), 1.39(9H, s), 1.95˜2.10(2H, m), 2.37(3H,s), 3.80(1H, dd), 4.42˜4.62(2H, m), 4.68(1H, d), 5.38(1H, d), 5.48(1H,d), 7.03˜7.15(3H, m), 7.19(1H, dd), 7.73(1H, dd), 7.82(1H, dd)

Step 2

Preparation of1-(2-thenoyl)methyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 131 was repeated except that1-(2-thenoyl)methyl-2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.95(9H, s), 1.53˜1.72(2H, m), 1.94˜2.08(2H, m),2.38(3H, s), 3.58˜3.80(2H, m), 4.48(1H, t), 4.51(1H, d), 5.54(1H, d),7.03˜7.13(3H, m), 7.20(1H, dd), 7.74(1H, dd), 7.84(1H, dd)

Step 3

Preparation of1-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

Step 2 of Example 126 was repeated except that1-(2-thenoyl)methyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.96(9H, s), 1.56(9H, s), 1.98˜2.13(2H, m), 2.37(3H,s), 3.87(1H, dd), 4.61(1H, t), 4.74(1H, d), 4.84(1H, dt), 5.37(1H, d),6.15(1H, d), 7.07˜7.16(4H, m), 7.22˜7.34(2H, m), 7.58˜7.71(3H, m),7.75˜7.82(2H, m)

Step 4

Preparation of3-[3-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureidolbenzoicacid

Step 4 of Example 133 was repeated except that1-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 247-249° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.95(9H, s), 1.93(1H, d), 2.05(1H, d), 2.38(3H, s),3.52-3.60(1H, m), 4.41-4.60(2H, m), 5.20(1H, d), 5.41(1H, d), 6.71(1H,d), 7.20-7.38(5H, m), 7.45-7.55(2H, m), 8.02(1H, t), 8.08(1H, dd),8.13(1H, dd), 9.00(1H, s), 12.80(1H, br)

MS(FAB)m/z: 577(MH⁺), 145(base)

IR(KBr)cm⁻¹:3392, 1702, 1649, 1632, 1561, 1233, 760

Example 136

Preparation of2-methyl-5-(3-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea

Step 3 of Example 131 was repeated except that1-(2-thenoyl)methyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that tert-butyl 5-amino-2-methylbenzoate was used instead of ethyl3-aminobenzoate, to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 0.94(9H, s), 1.52(9H, s), 1.92(1H, d), 2.04(1H, d),2.37(3H, s), 2.37(3H, s), 3.50-3.58(1H, m), 4.38-4.55(2H, m), 5.18(1H,d), 5.41(1H, d), 6.64(1H, d), 7.12(1H, d), 7.20-7.40(5H, m), 7.72(1H,d), 8.08(1H, dd), 8.13(1H, dd), 8.88(1H, s)

Step 2

Preparation of2-methyl-5-[3-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 133 was repeated except that1-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonyl-4-methylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 241-242° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.95(9H, s), 1.92(1H, d), 2.04(1H, d), 2.37(3H, s),2.41(3H, s), 3.50-3.58(1H, m), 4.40-4.58(2H, m), 5.19(1H, d), 5.40(1H,d), 6.64(1H, d), 7.13(1H, d), 7.20-7.40(5H, m), 7.87(1H, d), 8.08(1H,dd), 8.13(1H, dd), 8.86(1H, s), 12.70(1H, brs)

MS(FAB)m/z: 591(MH⁺), 136(base)

IR(KBr)cm⁻¹:3364, 3291, 1719, 1682, 1657, 1242, 737

Example 137

Preparation of2-methyl-5-[1-(2-toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.0 g) was suspended in 1,2-dichloroethane (20 ml), and2,2-dimethylbutanoyl chloride (538 mg) and pyridine (0.33 ml) were addedthereto to the suspension, and the mixture was refluxed for 2 hours.Methylene chloride was added to the reaction mixture, washed with waterand saturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, crystals soprecipitate were washed with ether, to thereby obtain 1.20 g of thetitle compound (Yield 89.8%).

¹H-NMR(CDCl₃) δ: 0.81(3H, t), 0.84(3H, s), 0.91(3H, s), 1.18-1.28(1H,m), 1.40(9H, s), 1.52-1.66(1H, m), 2.39(3H, s), 3.88(1H, dd),4.30-4.53(2H, m), 5.39(1H, d), 6.95(1H, brs), 7.03-7.15(2H, m), 7.86(1H,s)

Step 2

Preparation of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 1 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.84(3H, t), 0.90(3H, s), 0.96(3H, s), 1.15-1.45(1H,m), 1.40(9H, s), 1.57-1.75(1H, m), 2.37(3H, s), 2.60(3H, s), 3.95(1H,dd), 4.25(1H, t), 4.39(1H, d), 4.49-4.62(1H, m), 5.46-5.55(1H, m),5.55(1H, d), 7.02-7.14(3H, m), 7.25-7.37(2H, m), 7.41-7.49(1H, m),7.73-7.80(1H, m)

Step 3

Preparation of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 3 of Example 1 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.83(3H, t), 0.87(3H, s), 0.97(3H, s), 1.20-1.35(1H,m), 1.58-1.75(3H, m), 2.37(3H, s), 2.59(3H, s), 3.61-3.81(2H, m),4.25(1H, t), 4.33(1 H, d), 5.67(1H, d), 7.00(1H, brs), 7.05-7.14(2H, m),7.28-7.37(2H, m), 7.42-7.50(1H, m), 7.76-7.82(1H, m)

Step 4

Preparation of1-[1-(2-toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea

Step 3 of Example 131 was repeated except that1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that tert-butyl 5-amino-2-methylbenzoate was used instead of ethyl3-aminobenzoate, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.86(3H, t), 0.93(3H, s), 0.94(3H, s), 1.22-1.37(1H,m), 1.56(9H, s), 1.52-1.71(1H, m), 2.37(3H, s), 2.46(3H, s), 2.52(3H,s), 3.98(1H, dd), 4.34(1H, t), 4.38(1H, d), 4.82(1H, dt), 5.52(1H, d),6.03(1H, d), 6.98-7.32(7H, m), 7.37-7.46(2H, m), 7.60-7.72(2H, m)

Step 5

Preparation of2-methyl-5-[1-(2-toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 133 was repeated except that1-[1-(2-toluoylmethyl)-2-oxo-5-(2,2-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonyl-4-methylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 234-236° (decomposition)

¹H-NMR (DMSO-d₆) δ: 0.77(3H, t), 0.82(3H, s), 0.88(3H, s), 1.15-1.35(1H,m), 1.50-1.70(1H, m), 2.39(3H, s), 2.40(3H, s), 2.45(3H, s), 3.68(1H,dd), 4.24(1H, t), 4.52(1H, ddd), 4.89(1H, d), 5.41(1H, d), 6.66(1H, d),7.10-7.42(7H, m), 7.46-7.55(1H, m), 7.87(1H, d), 7.98(1H, d), 8.87(1H,s), 12.70(1H, br)

MS(FAB)m/z: 599(MH⁺), 119(base)

IR(KBr)cm⁻¹:3413, 3343, 2967, 1719, 1692, 1655, 1632, 1545, 752

Example 138

Preparation of3-[3-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 109 was repeated except that3-bromoacetyl-2,5-dimethylthiophene was used instead of2-bromo-2′-methylacetophenone, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.96(9H, s), 1.39(9H, s), 2.00(1H, d), 2.09(1H, d),2.36(3H, s), 2.43(3H, s), 2.70(3H, s), 3.81(1H, dd), 4.40-4.62(3H, m),5.21(1H, d), 5.50(1H, d), 6.98-7.13(4H, m)

Step 2

Preparation of1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 131 was repeated except that1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.95(9H, s), 1.63(2H, s), 1.97(1H, d), 2.06(1H, d),2.36(3H, s), 2.44(3H, s), 2.72(3H, s), 3.58-3.80 (2H, m), 4.37 (1H, d),4.47(1H, t), 5.38(1H, d), 6.97(1H, brs), 7.02-7.13(3H, m)

Step 3

Preparation of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

Step 2 of Example 126 was repeated except that1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.97(9H, s), 1.56(9H, s), 2.04(1H, d), 2.15(1H, d),2.37(3H, s), 2.39(3H, s), 2.64(3H, s), 3.83(1H, dd), 4.59(1H, t),4.62(1H, d), 4.85(1H, ddd), 5.24(1H, d), 6.15(1H, d), 7.01(2H, s),7.07-7.15(3H, m), 7.19-7.28(11H, m), 7.60(11H, dd), 7.77(1H, t)

Step 4

Preparation of3-[3-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 133 was repeated except that1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 231-233° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.95(9H, s), 1.97-2.11(2H, m), 2.37(3H, s), 2.41(3H,s), 2.59(3H, s), 3.52-3.60(1H, m), 4.40-4.60(2H, m), 5.05(1H, d),5.21(1H, d), 6.70(1H, d), 7.18-7.37(5H, m), 7.46-7.55(2H, m), 8.02(1H,t), 9.02(1H, s), 12.80(1H, br)

MS(FAB)m/z: 605(MH⁺), 139(base)

IR(KBr)cm⁻¹:3420, 3333, 2955, 1688, 1653, 1555, 754

Example 139

Preparation of2-methyl-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Step 3 of Example 95 was repeated except that tert-butyl5-amino-2-methylbenzoate was used instead of ethyl 3-aminobenzoate, tothereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.17(9H, s), 1.52(9H, s), 2.33(3H, s), 2.37(3H, s),3.51-3.63(1H, m), 3.96(1H, dd), 4.57(1H, ddd), 4.72(1H, d), 5.08(1H, d),6.63-6.87(3H, m), 7.00-7.24(6H, m), 7.38(1H, dd), 7.74(1H, d)

Step 2

Preparation of2-methyl-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-ylureido)benzoicacid

Step 4 of Example 133 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 248-250° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.17(9H, s), 2.33(3H, s), 2.41(3H, s), 3.57(1H, dd),3.96(1H, dd), 4.57(1H, ddd), 4,72(1H, d), 5.08(1H, d), 6.65(1H, d),6.73-6.87(3H, m), 7.00-7.24(6H, m), 7.38(1H, dd), 7.87(1H, d), 9.97(1H,s), 12.50-12.90(1H, br)

MS(FAB)m/z: 543(MH⁺), 154(base)

IR(KBr)cm⁻¹:3364, 3305, 2967, 1725, 1686, 1647, 1532, 1267, 760, 695

Example 140

Preparation of(+)-3-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

(±)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(10.0 g) was dissolved in ethyl acetate (150 ml), a solution (100 ml) of(+)-dibenzoyl-D-tartaric acid monohydrate (8.92 g) in ethyl acetate wasadded, and the mixture was stirred at room temperature overnight.Crystals so precipitated were collected by filtration, saturated aqueoussodium bicarbonate was added to the residue, and extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,the solvent was evaporated under reduced pressure, to thereby obtain4.44 g of the title compound as light-yellow-color amorphous.

Optical purity: 95%ee (Mosher method)

[α] D²⁷ (C=1.03, CHCl₃): +75.5°

Step 2

Preparation of(+)-1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea

Diphenylphosphoryl azide (6.60 g) and triethylamine (3.75 g) were addedto a solution of isophthalic acid benzyl ester (5.38 g) in anhydrousdioxane (50 ml), and the mixture was stirred at internal temperature 60°for 30 minutes and stirred at internal temperature 80° for one hour. Thereaction mixture was allowed to cool at room temperature,a solution of(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(3.0 g) in anhydrous dioxane (50 ml) was added thereto, and the mixturewas stirred at room temperature for 15 minutes. The reaction mixture wasconcentrated under reduced pressure, chloroform (200 ml) was added tothe residue, the organic layer was washed with saturated aqueous sodiumbicarbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography(NH-DM1020,produced by Fujisilicia Co. Ltd., n-hexane:ethyl acetate=2:1), tothereby obtain 4.08 g of the title compound (Yield 85.2%).

¹H-NMR(CDCl₃) δ: 0.96(9H, s), 2.04(1H, d), 2.17(1H, d), 2.37(3H, s),2.47(3H, s), 3.84(1H, dd), 4.61(1H, t), 4.67(1H, d), 4.87(1H, dt),5.32(1H, d), 6.36(1H, d), 7.02(1H, s), 7.11(2H, s), 7.17-7.45(9H, m),7.49(1H, s), 7.60-7.72(3H, m), 7.88-7.93(1H, m)

[α] D²⁷ (C=1.034, CHCl₃): +34.8°

Step 3

Preparation of(+)-3-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

(+)-1-[1-(2-Toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonylphenyl)urea(4.0 g) was dissolved in ethanol (50 ml), 10% palladium carbon (400 mg)was added thereto, the mixture was stirred for 2 hours and 30 minutes atroom temperature under hydrogen atmosphere. The reaction mixture wasfiltrated, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel columnchromatography(chloroform:methanol=20:1), subsequently isopropyl etherwas added to the residue for trituration, collected by filtration, tothereby obtain 2.82 g of the titled compound (Yield 81.5%).

Melting point: 174-179° C. (forming)

Optical purity: 97.6%ee (the ee value was determined by High PerformanceLiquid Chromatography)

MS(FAB)m/z: 585(MH⁺), 133(base)

[α] D²⁷ (C=1.054, CHCl₃): +45.2°

Example 141

Preparation of(+)-2-methyl-5-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of(+)-1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonyl-4-methylphenyl)urea

Step 4 of Example 109 was repeated except that(+)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that tert-butyl 5-amino-2-methylbenzoate was used instead of ethyl3-aminobenzoate, to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.96(9H, s), 1.56(9H, s), 2.03(1H, d), 2.15(1H, d),2.38(3H, s), 2.47(3H, s), 2.49(3H, s), 3.85(1H, dd), 4.57(1H, t),4.70(1H, d), 4.85(1H, ddd), 5.29(1H, d), 6.05(1H, d), 7.00-7.13(5H, m),7.20-7.30(2H, m), 7.37-7.45(2H, m), 7.62(1H, d), 7.69(1H, d)

[α] D (C=1.043, CHCl₃): +28.1°

Step 2

Preparation of(+)-2-methyl-5-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 133 was repeated except that(+)-1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-benzyloxycarbonyl-4-methylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound as amorphous.

Optical purity: 98.6%ee (the ee value was determined by High PerformanceLiquid Chromatography)

MS(FAB)m/z: 599(MH⁺), 119(base)

[α] D (C=1.01, MeOH): +39.6°

Example 142

Preparation of(+)-3-[3-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of(+)-1-(2-thenoyl)methyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 140 was repeated except that(±)-1-(2-thenoyl)methyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of(±)-1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Optical purity: 95%ee (the ee value was determined by ¹H-NMR, after thetitle compound was converted into Mosher ester)

[α] D (C=1.02, CHCl₃): +106.6°

Step 2

Preparation of(+)-1-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

In a similar manner to Step 3 of Example 135, by use of(+)-1-(2-thenoyl)methyl-2-oxo-3-amino-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

[α] D (C=1.06, CHCl₃): +58.3°

Step 3

Preparation of(+)-3-[3-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

In a similar manner to Step 4 of Example 135, by use of(+)-1-[1-(2-thenoyl)methyl-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 170-180° C. (forming)

Optical purity: 99.5%ee (the ee value was determined by High PerformanceLiquid Chromatography)

MS(FAB)m/z: 577(MH⁺), 154(base)

[α] D (C=1.07, CHCl₃): +65.40°

Example 143

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of(R)-(−)-2-tert-butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid

(R)-2-tert-Butoxycarbonylamino-3-aminopropionic acid (5 g) and potassiumcarbonate (6.77 g) were added to a solution of 2-fluoronitrobenzene(3.45 g) in N,N-dimethylformamide (60 ml), and the mixture was stirredovernight at 70° C. After the reaction mixture was allowed to cool, thereaction mixture was poured into ice-water and washed with ethylacetate. The water layer was adjusted to pH 3 with 1N hydrochloric acid,extracted with ethyl acetate. This organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. Hexane was added to the residuefor crystallization, collected by filtration,to thereby obtain 7.9 g ofthe title compound (Yield 99%).

[α] D²⁵ (C=1.00, CHCl₃): −145°

Step 2

Preparation of(R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

10% palladium carbon (1 g) was added to a solution of(R)-(−)-2-tert-butoxycarbonylamino-3-(2-nitrophenylamino)propionic acid(7.6 g) in tetrahydrofuran (100 ml), and the mixture was stirred underhydrogen atmosphere at room temperature for 3 hours. The reactionmixture was filtrated, and the filtrate was concentrated under reducedpressure, to thereby obtain(R)-2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid. Theresidue was dissolved in toluene (100 ml), the solution was refluxedovernight. After allowed to cool, the reaction mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography(ethyl acetate:n-hexane=1:1), to thereby obtain 5.16 g ofthe title compound (Yield 80%).

[α] D²⁵ (C=1.0, CHCl₃): +7.21°

Optical purity: 98%ee (the ee value was determined by High PerformanceLiquid Chromatography)

Step 3

Preparation of(3R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

3-Bromocyclohexene (7.06 g) and sodium bicarbonate (3.68 g) were addedto a solution of(R)-(+)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(6.08 g) in anhydrous N,N-dimethylformamide (50 ml), and the mixture wasstirred at 50° C. for one hour. The reaction mixture was allowed tocool, ice-water was added, and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure,the residuewas purified by silica gel column chromatography(ethylacetate:n-hexane=1:3), to thereby obtain 7.84 g of the titled compound.

[α] D²⁵ (C=1.00, CHCl₃): −179°

Step 4

Preparation of(R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 1 of Example 118 was repeated except that(3R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

[α] D²³ (C=1.02, CHCl₃): −188°

Step 5

Preparation of(R)-(−)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

4N HCl-dioxane (10 ml) was added to a solution of(R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(5.11 g) in ethanol (15 ml), and the mixture was stirred at 50: for onehour. After allowed to cool, the reaction mixture was concentrated underreduced pressure, the residue was neutralized with saturated aqueoussodium bicarbonate, and extracted with chloroform. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, diisopropyl ether wasadded to crystals so precipitated, washed, and collected by filtration.This was recrystallized from a mixed solvent of ethanol and diisopropylether, to thereby obtain 2.1 g of the titled compound.

Melting point: 180-182° C.

¹H-NMR(CDCl₃) δ: 1.06-2.07(12H, m), 3.17-3.32(2H, m), 3.49-3.62(2H, m),6.90-6.99(2H, m), 7.09-7.18(2H, m), 7.45(1H, s)

[α] D²⁵ (C=1.04, CHCl₃): −163°

Optical purity: 99%ee over (the ee value was determined by HighPerformance Liquid Chromatography)

Step 6

Preparation of(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Triphosgene (1.8 g) was added to a solution of tert-butyl3-aminobenzoate (3.13 g) in anhydrous tetrahydrofuran (200 ml) underice-cooling, and then triethylamine (7.25 ml) was added five times each1.45 ml over 15 minutes, and the mixture was stirred at room temperaturefor 5 minutes. Subsequently(R)-(−)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(4 g) was added under ice-cooling. The mixture was stirred at roomtemperature for one hour, the reaction mixture was concentrated underreduced pressure. Ice-water was added to the residue, extracted withmethylene chloride,the organic layer was washed with saturated brine.After dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure. Diisopropyl ether was added to the residue,crystals were collected by filtration, to thereby obtain 7.38 g of thetitled compound.

¹H-NMR(DMSO-d₆) δ: 1.10-2.03(19H, m), 3.18-3.36(2H, m), 3.53(1H, dd),4.27-4.36(1H, m), 6.59(1H, d), 6.97-7.03(2H, m), 7.10-7.22(2H, m),7.32(1H, t), 7.41-7.47(1H, m), 7.52-7.58(1H, m), 7.92(1H, t), 9.08(1H,s), 9.85(1H, s)

[α] D²⁵ (C=0.91, MeOH): −148°

Step 7

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Bromomethyl tert-butylketone (2.95 g), potassium iodide (125 mg), tetran-butylammonium bromide (145 mg) and potassium carbonate (2.07 g) wereadded to a solution of(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea(7.18 g) in dimethylsulfoxide (100ml), the mixture was stirred for2hours at room temperature. The reaction mixture was poured intoice-water, extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, the residue was purified bysilica gel column chromatography(ethyl acetate:n-hexane=1:2), to therebyobtain 8.22 g of the titled compound (Yield 95%).

¹H-NMR(CDCl₃) δ: 1.00-2.04(28H, m), 3.16-3.28(1H, m), 3.89(1H, dd),3.64(1H, dd), 4.28(1H, d), 4.67-4.78(1H, m), 5.14(1H, d), 6.33(1H, d),6.97-7.06(2H, m), 7.14-7.27(4H, m), 7.50-7.59(2H, m), 7.81(1H, t)

[α] D²⁵ (C=1.05, CHCl₃): −63.0°

Step 8

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Trifluoroacetic acid (40 ml) was added to a solution of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea(8 g) in methylene chloride (40 ml), the mixture was stirred for onehour at room temperature. The reaction mixture was concentrated underreduced pressure, a mixed solvent (32 ml) of diisopropyl ether andethanol (15:1) was added to the residue for crystallization, collectedby filtration, to thereby obtain 6.35 g of the title compound (Yield88%).

Melting point: 159-161° C.

MS(FAB)m/z: 521(MH⁺), 543(M+Na)⁺

IR(KBr)cm⁻¹:3370, 2932, 2855, 1727, 1644, 1561, 1497

[α] D²⁵ (C=1.01, CHCl₃): −148°

Optical purity: 99.0%ee over (the ee value was determined by HighPerformance Liquid Chromatography)

Example 144

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-phenylurea

Step 1

Phenyl isocyanate (110 mg) was added to a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(300 mg) in anhydrous tetrahydrofuran (10 ml), the mixture was stirredfor 10 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure, etanol was added to the residue forcrystallization, collected by filtration, to thereby obtain 336 mg ofthe title compound (Yield 83.9%).

Melting point: 247-251° C.

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.10-1.82(9H, m), 1.93-2.05(1H, m),3.15-3.47(3H, m), 4.31-4.45(1H, m), 4. 39(1H, d), 5.13(1H, d), 6.57(1H,d), 6.84-6.92(1H, m), 6.98-7.03(1H, m), 7.09(1H, ddd), 7.17-7.35(6H, m),8.81(1H, s)

MS(FAB)m/z: 477(MH⁺), 133(base)

IR(KBr)cm⁻¹:3378, 2936, 1717, 1684, 1657, 1597, 1547, 1499, 1219, 752,691

Example 145

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(1-naphthyl)urea

Example 144 was repeated except that 1-naphthyl isocyanate was usedinstead of phenyl isocyanate, to thereby obtain the title compound.

Melting point: 200-203° C.

¹H-NMR(DMSO-d₆) δ: 1.19(9H, s), 1.10-1.83(9H, m), 1.93-2.07(1H, m),3.15-3.54(3H, m), 4.40(1H, d), 4.39-4.51 (1H, m), 5. 16(1H, d),6.99-7.14(2H, m), 7.17-7.32(3H, m), 7.38(11H, t), 7.58(3H, m),7.84-7.97(2H, m), 8.08-8.17(1H, m), 8.87(1H, s)

MS(FAB)m/z: 527(MH⁺), 133(base)

IR(KBr)cm⁻¹:3389, 3343, 2936, 1717, 1667, 1545, 1499, 1215, 1080, 764

Example 146

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-chlorophenyl)urea

Example 144 was repeated except that m-chlorophenyl isocyanate was usedinstead of phenyl isocyanate, to thereby obtain the title compound.

Melting point: 245-248° (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.12-1.82(9H, m), 1.93-2.05(1H, m),3.15-3.50(3H, m), 4.30-4.45(1H, m), 4.39(1H, d), 5.12(1H, d), 6.65(1H,d), 6.90-7.04(2H, m), 7.06-7.14(2H, m), 7.18-7.32(3H, m), 7.58(1H, t),9.47(1H, s)

MS(FAB)m/z: 511(MH⁺), 133(base)

IR(KBr)cm⁻¹:3368, 2936, 1721, 1686, 1657, 1595, 1545, 1233, 860, 681

Example 147

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-chlorophenyl)urea

Example 144 was repeated except that p-chlorophenyl isocyanate was usedinstead of phenyl isocyanate, to thereby obtain the title compound.

Melting point: 258-260° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.10-1.82(9H, m), 1.92-2.05(1H, m),3.15-3.46(3H, m), 4.30-4.44(1H, m), 4.39(1H, d), 5.12(1H, d), 6.60(1H,d), 6.98-7.03(1H, m), 7.09(1H, ddd), 7.20-7.38(6H, m), 8.96(1H, s)

MS(FAB)m/z: 511(MH⁺), 133(base)

IR(KBr)cm⁻¹:3355, 2932, 1719, 1688, 1655, 1597, 1536, 1495, 1233, 830,766

Example 148

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-fluorophenyl)urea

Example 144 was repeated except that p-fluorophenyl isocyanate was usedinstead of phenyl isocyanate, to thereby obtain the title compound.

Melting point: 236-238° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.12-1.82(9H, m), 1.93-2.05(1H, m),3.15-3.46(3H, m), 4.30-4.45 (2H, m), 5.13(1H, d), 6.54(1H, d),6.98-7.13(4H, m), 7.20-7.37(4H, m), 8.86(1H, s)

MS(FAB)m/z: 495(MH⁺), 133(base)

IR(KBr)cm⁻¹:3368, 2936, 1719, 1686, 1655, 1549, 1507, 1217, 833

Example 149

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-bromophenyl)urea

Example 144 was repeated except that p-bromophenyl isocyanate was usedinstead of phenyl isocyanate,to thereby obtain the title compound.

Melting point: 264-266° C. (decomposition)

¹H-NMR(DMSO-d6) δ: 1.18(9H, s), 1.10-1.82(9H, m), 1.92-2.05(1H, m),3.14-3.47(3H, m), 4.30-4.45(2H, m), 5.12(1H, d), 6.60(1H, d),6.97-7.03(1H, m), 7.09(1H, ddd), 7.20-7.41(6H, m), 8.96(1H, s)

MS(FAB)m/z: 555(MH⁺), 133(base)

IR(KBr)cm⁻¹:3366, 2932, 1719, 1686, 1655, 1534, 1491, 1247, 1076, 826

Example 150

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-trifluoromethylphenyl)urea

Example 144 was repeated except that 3-trifluoromethylphenyl isocyanatewas used instead of phenyl isocyanate, to thereby obtain the titlecompound.

Melting point: 245-247° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.10-1.82(9H, m), 1.93-2.06(1H, m),3.15-3.48(3H, m), 4.31-4.47(2H, m), 5.13(1H, d), 6.70(1H, d),6.98-7.04(1H, m), 7.10(1H, ddd), 7.20-7.32(3H, m), 7.35-7.49(2H, m),7.92(1H, s), 9.21(1H, s)

MS(FAB)m/z: 545(MH⁺), 133(base)

IR(KBr)cm⁻¹:3341, 2934, 1719, 1684, 1655, 1549, 1337, 1127, 695

Example 151

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methoxyphenyl)urea

Step 3 of Example 131 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that m-anisidine was used instead of ethyl 3-aminobenzoate, tothereby obtain the title compound. Melting point: 234-235° C.

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.10-1.82(9H, m), 1.93-2.05(1H, m),3.15-3.46(3H, m), 3.67(3H, s), 4.30-4.44(2H, m), 5.12(1H, d), 6.47(1H,dd), 6.55(1H, d), 6.72-6.79(1H, m), 6.97-7.14(4H, m), 7.21-7.32(2H, m),8.82(1H, s)

MS(FAB)m/z: 507(MH⁺), 154(base)

IR(KBr)cm⁻¹:3360, 2936, 1717, 1682, 1655, 1595, 1541, 1157, 864, 758

Example 152

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-nitrophenyl)urea

Step 3 of Example 131 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,andthat m-nitroaniline was used instead of ethyl 3-aminobenzoate, tothereby obtain the title compound.

Melting point: 248-250° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.08-1.82(9H, m), 1.94-2.06(1H, m),3.13-3.37(2H, m), 3.40-3.50(1H, m), 4.31-4.46(2H, m), 5.13(1H, d),6.74(1H, d), 6.98-7.06(1H, m), 7.11(1H, ddd), 7.21-7.32(2H, m),7.45-7.57(2H, m), 7.75(1H, dt), 8.44(1H, t), 9.36(1H, s)

MS(FAB)m/z: 522(MH⁺), 133(base)

IR(KBr)cm⁻¹:3347, 1713, 1688, 1655, 1347, 1082

Example 153

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-[3-(tetrazol-5-yl)phenyl]urea

Step 3 of Example 131 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,andthat 5-(3-aminophenyl) tetrazole was used instead of ethyl3-aminobenzoate, to thereby obtain the title compound.

Melting point: 224-226° C. (forming)

¹H-NMR(DMSO-d6) δ: 1.18(9H, s), 1.10-1.82(9H, m), 1.93-2.06(1H, m),3.15-3.53(3H, m), 4.34-4.47(2H, m), 5.13(1H, d), 6.68(1H, d),6.98-7.05(1H, m), 7.10(1H, ddd), 7.21-7.32(2H, m), 7.38-7.49(3H, m),7.51-7.58(1H, m), 8.13(1H, s), 9.10(1H, s)

MS(FAB)m/z: 545(MH⁺), 154(base)

IR(KBr)cm⁻¹:3332, 2932, 1716, 1644, 1539, 1252, 1080, 739

Example 154

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-pyridyl)urea

Step 3 of Example 131 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that 3-aminopyridine was used instead of ethyl 3-aminobenzoate, tothereby obtain the title compound.

Melting point: 239-241° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.93-2.04(9H, m), 3.15-3.48(3H, m),4.31-4.45(2H, m), 5.12(1H, d), 6.70(1H, d), 6.97-7.03(1H, m), 7.10(1H,ddd), 7.20-7.31(3H, m), 7.79(1H, dq), 8.11(1H, dd), 8.46(1H, d),9.01(1H, s)

MS(FAB)m/z: 478(MH⁺), 121(base)

IR(KBr)cm⁻¹:3337, 2934, 1717, 1686, 1597, 1221, 758, 708

Example 155

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylaceticacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenylmethyl)urea

Step 3 of Example 131 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,and that tert-butyl 3-aminophenylacetate was used instead of ethyl3-aminobenzoate, to thereby obtain the title compound.

¹H-NMR(DMSO-d6) δ: 1.18(9H, s), 1.38(9H, s), 1.08-1.82(9H, m),1.92-2.05(1H, m), 3.15-3.48(5H, m), 4.31-4.45(2H, m), 5.12(1H, d),6.56(1H, d), 6.76(1H, d), 6.98-7.30(7H, m), 8.80(1H, s)

Step 2

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylaceticacid

Step 4 of Example 133 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 184-190° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.12-1.82(9H, m), 1.93-2.05(1H, m),3.13-3.46(5H, m), 4.30-4.45(2H, m), 5.11(1H, d), 6.55(1H, d), 6.78(1H,d), 6.98-7.30(7H, m), 8.80(1H, s), 12.2(1H, br)

MS(FAB)m/z: 535(MH⁺), 133(base)

IR(KBr)cm⁻¹:3357, 2934, 1719, 1655, 1497, 1238, 760

Example 156

Preparation of3-[3-[(3R)-1-tert-butylcarbonylmethyl-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of(3R)-2-oxo-3-tert-butoxycarbonylamino-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Sodium bicarbonate (2.02 g) and (1s)-10-chloro-2-pinene (4.1 g) wereadded to a solution of(R)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.22 g) in anhydrous methanol (40 ml), and the mixture was refluxedovernight. The reaction mixture was concentrated under reduced pressure,water (200 ml) was added, and extracted with ethyl acetate (200 ml)twice. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel columnchromatography(n-hexane:ethyl acetate=4:1), to thereby obtain 2.03 g ofthe titled compound.

¹H-NMR(CDCl₃) δ: 0.82(3H, s), 0.80-0.92(1H, m), 1.18(3H, s), 1.41(9H,s), 2.00-2.06(2H, m), 2.15-2.25(3H, m), 3.68-3.78(1H, m), 4.38-4.50(1H,m), 5.37-5.42(1H, m), 5.52(1H, d), 6.92-7.05(3H, m), 7.08-7.18(1H, m),7.87(1H, brs)

Step 2

Preparation of(3R)-2-oxo-3-amino-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 131 was repeated except that(3R)-2-oxo-3-tert-butylcarbonylamino-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.82(1H, d), 0.82(3H, s), 1.18(3H, s), 1.69(2H, brs),1.98-2.08(2H, m), 2.15-2.25(3H, m), 3.28(1H, dd), 3.38(1H, dd), 3.45(1H,dd), 3.56(1H, dd), 3.73(1H, dd), 5.36-5.43(1H, m), 6.92-7.18(4H, m),7.79(1H, s)

Step 3

Preparation of(3R)-1-[2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

Step 3 of Example 131 was repeated except that(3R)-2-oxo-3-amino-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-methyl-N-phenylcarbamoylmethyl)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 0.81(3H, s), 0.80-0.92(1H, m), 1.18(3H, s), 1.56(9H,s), 2.00-2.08(2H, m), 2.15-2.25(3H, m), 3.37-3.52 (2H, m), 3.66 (1H,dd), 3.71-3.82 (1H, m), 4.74(1H, ddd), 5.38-5.44(1H, m), 6.18(1H, d),6.94-7.10(3H, m), 7.13-7.22(1H, m), 7.28-7.34(1H, m), 7.59(1H, dt),7.77-7.92(4H, m)

Step 4

Preparation of1-[(3R)-1-tert-butylcarbonylmethyl-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

Step 2 of Example 1 was repeated except that1-[(3R)-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,that bromomethyl-tert-butylketone was used instead of2-bromo-2′-methylacetophenone, and that N,N-dimethyl acetamide was usedinstead of tetrahydrofuran as solvent, to thereby obtain the titlecompound.

¹H-NMR(CDCl₃) δ: 0.75(1H, d), 0.83(3H, s), 1.23(9H, s), 1.25(3H, s),1.56(9H, s), 2.00-2.25(5H, m), 3.30-3.55(3H, m), 3.71-3.81(1H, m),4.15(1H, d), 4.74(1H, dt), 5.17(1H, d), 5.37-5.42(1H, m), 6.27(1H, d),6.90(1H, s), 6.97-7.10(3H, m), 7.15-7.28(2H, m), 7.52(1H, dq), 7.58(1H,dt), 7.80(1H, t)

Step 5

Preparation of3-[3-[(3R)-1-tert-butylcarbonylmethyl-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 133 was repeated except that1-[(3R)-1-tert-butylcarbonylmethyl-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound as amorphous.

¹H-NMR(CDCl₃) δ: 0.78-0.92(1H, m), 0.84(3H, s), 1.27(3H, s), 1.29(9H,s), 2.02-2.27(5H, m), 3.34-3.48(2H, m), 3.63(1H, dd), 3.70-3.80(1H, m),4.10(1H, d), 4.69(1H, ddd), 5.22(1H, d), 5.38-5.44(1H, m), 7.00-7.12(3H,m), 7.18-7.26(1H, m), 7.31-7.43(2H, m), 7.60(1H, d), 7.71(1H, s),8.19(1H, s), 8.34-8.41(1H, m), 10.80-11.20(1H, br)

MS(FAB)m/z: 573(MH⁺), 79(base)

IR(KBr)cm⁻¹:3376, 2969, 1725, 1647, 1555, 1219, 758

Example 157

Preparation of 3-[3-[(3R)-1-tert-butylcarbonylmethyl-2-oxo-5-[(1S, 2R,5S)-pinan-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Platinum oxide (8 mg) was added to a solution of3-[3-(3R)-1-tert-butylcarbonylmethyl-2-oxo-5-[(1S)-2-pinen-10-yl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid (80 mg) in anhydrous tetrahydrofuran (2 ml) was added, and themixture was stirred for one hour and 30 minutes under hydrogenatmosphere, under ambient pressure. The reaction mixture was filtratedthrough a pad of Celite, the filtrate was concentrated under reducedpressure, n-hexane and isopropyl ether were added to the residue fortrituration, collected by filtration, to thereby obtain 55 mg of thetitled compound as amorphous.

¹H-NMR(CDCl₃) δ: 0.87(1H, d), 0.97(3H, s), 1.20(3H, s), 1.30(9H, s),1.45-1.72(3H, m), 1.80-1.98(4H, m), 2.26-2.40(2H, m), 2.92(1H, dd),3.21(1H, dd), 3.41(1H, dd), 3.60-3.70(1H, m), 4.07(1H, d), 4.69(1H,ddd), 5.29(1H, d), 6.98-7.12(3H, m), 7.20-7.28(1H, m), 7.30-7.42(2H, m),7.60(1H, d), 7.71(1H, s), 8.21(1H, s), 8.37(1H, dd), 10.60-11.20(1H, br)

IR(KBr)cm⁻¹:3372, 2936, 1725, 1647, 1593, 1554, 1219, 756

Example 158

Preparation of3-[3-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-cyclohexylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Bromomethylcyclohexylketone (861 mg), potassium iodide (23 mg), tetran-butylammonium bromide (27 mg) and potassium carbonate (464 mg) wereadded to a solution of2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1 g) in dimethylsulfoxide (10 ml), the mixture was stirred overnight atroom temperature. Ice-water was added to the reaction mixture, extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography(ethyl acetate:n-hexane=1:5) and subsequently purified bysilica gel column chromatography(silica gel NH-DM1020, produced byFujisilicia Co. Ltd., ethyl acetate:n-hexane=1:5), to thereby obtain 500mg of the title compound.

¹H-NMR(CDCl₃) δ: 1.12-2.08(29H, m), 2.44-2.56(1H, m), 3.13-3.25(1H, m),3.27(1H, dd), 3.59(1H, dd), 4.14(1H, d), 4.37-4.48(1H, m), 4.90(1H, d),5.54(1H, d), 6.96-7.03(2H, m), 7.12-7.19(2H, m)

Step 2

Preparation of1-cyclohexylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

4N HCl-dioxane (10 ml) was added to a solution of1-cyclohexylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(500 mg) in ethanol (10 ml), and the mixture was stirred at 50° C. forone hour. The reaction mixture was concentrated under reduced pressure,the residue was neutralized with saturated aqueous sodium bicarbonate,extracted with methylene chloride. The organic layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, to thereby obtain 400 mg of the title compound.

¹H-NMR(CDCl₃) δ: 1.11-1.90(20H, m), 1.94-2.07(2H, m), 2.46-2.58(1H, m),3.12-3.21(1H, m), 3.22(1H, dd), 3.39(1H, dd), 3.51-3.60(1H, m), 4.05(1H,d), 5.02(1H, d), 6.97-7.05 (2H, m), 7.15-7.27(2H, m)

Step 3

Preparation of1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Triphosgene (122 mg) was added to a solution of tert-butyl3-aminobenzoate (213 mg) in anhydrous tetrahydrofuran (30 ml) at 0° C.,triethylamine (0.49 ml) was added thereto at 0° C. five times each 98 μlover 15 minutes. After the mixture was stirred at room temperature for 5minutes, a solution of1-cyclohexylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(395 mg) in anhydrous tetrahydrofuran (10 ml) was added at 0° C., theresultant mixture was stirred at room temperature for one hour. Thereaction mixture was concentrated under reduced pressure, and water wasadded to the residue, extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, diisopropylether was added to the residue for crystallization, collected byfiltration, to thereby obtain 570 mg of the title compound (Yield: 92%).

¹H-NMR(CDCl₃) δ: 1.07-1.93(28H, m), 1.97-2.08(1H, m), 2.46(1H, tt),3.14-3.25(1H, tt), 3.38(1H, dd), 3.66(1H, dd), 4.29(1H, d), 4.72(1H,dt), 4.88(1H, d), 6.13(1H, d), 6.97-7.06(3H, m), 7.15-7.21(2H, m),7.24-7.31(1H, m), 7.60(1H, d), 7.63(1H, d), 7.78(1H, t)

Step 4

Preparation of3-[3-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Trifluoroacetic acid (5 ml) was added to a solution of1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea(560 mg) in methylene chloride (5 ml), the mixture was stirred at roomtemperature for one hour. The reaction mixture was concentrated underreduced pressure, etanol was added to the residue for crystallization,collected by filtration, to thereby obtain 330 mg of the title compound.

Melting point: 220-222° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.05-2.05(20H, m), 2.50-2.63(1H, m), 3.16-3.50(3H,m), 4.31-4.44(2H, m), 4.89(1H, d), 6.60(1H, d), 7.02-7.15(2H, m),7.21-7.36(3H, m), 7.46-7.52(2H, m), 7.98(1H, t), 9.01(1H, s), 12.80(1H,brs)

MS(FAB)m/z: 547(MH⁺), 569(M+Ha)⁺

IR(KBr)cm⁻¹:3351, 3291, 2932, 2857, 1727, 1689, 1651, 1553

Example 159

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclopentyl-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Sodium bicarbonate (1.68 g) and 3-bromocyclopentene (2.94 g) were addedto a solution of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.77 g) in dimethylformamide (20 ml), the mixture was stirred at 50° C.for one hour. After the reaction mixture was allowed to cool, ice-waterwas added thereto, extracted with ethyl acetate,the organic layer waswashed with saturated brine. The resultant mixture was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(ethyl acetate:n-hexane=1:2), diisopropyl ether was addedto the residue for crystallization, collected by filtration, to therebyobtain 1.9 g of the title compound as the mixture of diastereomercompounds.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 2.10-2.26(2H, m), 2.38-2.53(2H, m),3.15-3. 26 (1H, m), 3.49-3.61(1H, m), 4.39-4.60(2H, m), 5.48(1H, d),5.62-5.66(1H, m), 5.93-5.98(1H, m), 6.91-7.01(2H, m), 7.10-7.20(2H, m),7.47(1H, s)

Step 2

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Platinum oxide (100 mg) was added to a solution of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclopenten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.8 g) in anhydrous tetrahydrofuran (20 ml), the mixture was stirred atroom temperature under ambient pressure under hydrogen atmosphere for 2hours. The reaction mixture was filtrated through a pad of Celite, thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography(ethylacetate:n-hexane=1:2). Diisopropyl ether was added to the residue forcrystallization, to thereby obtain 1.2 g of the title compound.

¹H-NMR(CDCl₃) δ: 1.40(9H, s), 1.49-2.04(8H, m), 3.33(1H, dd), 3.51(1H,dd), 3.59-3.70(1H, m), 4.30-4.42(1H, m), 5.51(1H, d), 6.94-7.04(2H, m),7.10-7.21(2H, m), 7.50(1H, s)

Step 3

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Bromomethyl tert-butylketone (684 mg), potassium iodide (26.4 mg), tetran-butylammonium bromide (30.8 mg) and potassium carbonate (528 mg) wereadded successively to a solution of2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.1 g) in N,N-dimethylformamide (30 ml), the mixture was stirred atroom temperature for 2 hours. Ice-water was added to the reactionmixture, extracted with ethyl acetate, the organic layer was washed withsaturated brine. The resultant mixture was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and n-hexanewas added to the residue for crystallization, collected by filtration,to thereby obtain 1.07 g of the title compound.

¹H-NMR(CDCl₃) δ: 1.26(9H, s), 1.38(9H, s), 1.49-2.03(8H, m), 3.26(1H,dd), 3.45(1H, dd), 3.59(1H, q), 4.25(1H, d), 4.31-4.42(1H, m), 5.22(1H,d), 5.57(1H, d), 6.94-7.05(2H, m), 7.09-7.21(2H, m)

Step 4

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 158 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-cyclohexylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.28(9H, s), 1.50-2.04(10H, m), 3.16-3.27(2H, m),3.47-3.64(2H, m), 4.02(1H, d), 5.33(1H, d), 6.93-7.06(2H, m),7.11-7.22(2H, m)

Step 5

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Step 3 of Example 158 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5benzodiazepinewas used instead of1-cyclohexylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.22(9H, s), 1.46-2.03(17H, m), 3.37-3.52(2H, m),3.53-3.66(1H, m), 4.32(1H, d), 4.65(1H, dt), 5.13(1H, d), 6.13(1H, d),6.97-7.12(3H, m) 7.29(3H, m), 7.56-7.63(2H, m), 7.80(1H, t)

Step 6

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 4 of Example 158 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.45-2.05(8H, m), 3.17-3.39(2H, m),3.58-3.71(1H, m), 4.26-4.37(1H, m), 4.41(1H, d), 5. 18(1H, d), 6.62(1H,d), 7.01(1H, d), 7.08-7.18(1H, m), 7.25-7.35(3H, m), 7.44-7.53(2H, m),7.96-8.00(1H, m), 9.01(1H, s), 12.5(1H, brs)

MS(FAB)m/z: 507(MH⁺), 529(M+Na)⁺

IR(KBr)cm⁻¹:3367, 2870, 1719, 1690, 1655, 1557

Example 160

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohepten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Sodium bicarbonate (1.6 g) and 3-bromocycloheptene (3.33 g) were addedto a solution of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.77 g) in N,N-dimethylformamide (20 ml), the mixture was stirred at50° C. for one hour. After the reaction mixture was allowed to cool,ice-water was added thereto, extracted with ethyl acetate, the organiclayer was washed with saturated brine. The resultant mixture was driedover anhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography(ethyl acetate:n-hexane=1:2), diisopropyl ether was addedto the residue for crystallization, and collected by filtration, tothereby obtain 2.1 g of the title compound as the mixture ofdiastereomer compounds.

¹H-NMR(CDCl₃) δ: 1.22-2.30(17H, m), 3.24-3.44(1H, m), 3.78-3.89(1H, m),3.90-4.05(1H, m), 4.40-4.57(1H, m), 5.48-5.57(1H, m), 5.75-6.17(2H, m),6.89-6.99(2H, m), 7.06-7.17(2H, m), 7.48-7.55(1H, m)

Step 2

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 159 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohepten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclopenten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.20-2.10(21H, m), 3.27-3.40(2H, m), 3.74(1H, dd),4.39-4.50(1H, m), 5.53(1H, d), 6.90-7.18(4H, m), 7.64(1H, s)

Step 3

Preparation of1-tert-butylcarbonylamino-2-oxo-3-tert-butoxycarbonylamino-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 3 of Example 159 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.20-2.08(30H, m), 3.24(1H, dd), 3.26-3.39(1H, m),3.68(1H, dd), 4.12(1H, d), 4.40-4.52(1H, m), 5.14(1H, d), 5.56(1H, d),6.92-7.00(2H, m), 7.02-7.08(1H, m), 7.11-7.19(1H, m)

Step 4

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 158 was repeated except that1-tert-butylcarbonylamino-2-oxo-3-tert-butoxycarbonylamino-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-cyclohexylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.27(9H, s), 1.32-2.06(14H, m), 3.18(1H, dd),3.27-3.38(1H, m), 3.50(1H, dd), 3.55-3.65 (1H, m), 4.01 (1H, d),5.27(1H, d), 6.90-7.01(2H, m), 7.04-7.09(1H, m), 7.13-7.20(1H, m)

Step 5

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Step 3 of Example 158 was repeated except that1-tert-butoxycarbonylmethyl-2-oxo-3-amino-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-cyclohexylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.21(9H, s), 1.30-2.08(21H, m), 3.30-3.41(2H, m),3.74(1H, dd), 4.28(1H, d), 4.68-4.79(1H, m), 5.09(11H, d), 6.15(11H, d),6.95-7.03(3H, m), 7.05-7.12(1H, m), 7.15-7.29(2H, m), 7.55-7.63(2H, m),7.80(1H, t)

Step 6

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 4 of Example 158 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-cycloheptyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 253-255° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.28-2.03(12H, m), 3.17-3.45(2H, m),3.48-3.56(1H, m), 4.34-4.45(2H, m), 5.10(1H, d), 6.61(1H, d),6.97-7.17(3H, m), 7.21-7.36(2H, m), 7.45-7.52(2H, m), 7.99(1H, t),9.03(1H, s), 12.80(1H, brs)

MS(FAB)m/z: 535(MH⁺), 557(M+Na)⁺

IR(KBr)cm⁻¹:3357, 2934, 2859, 1721, 1688, 1655, 1595, 1557

Example 161

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-(2-cycloocten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Sodium bicarbonate (606 mg) and 3-bromocyclooctene (1.36 g) were addedto a solution of2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1 g) in N,N-dimethylformamide (20 ml), the mixture was stirredovernight at 80° C. After the reaction mixture was allowed to cool,ice-water was added thereto, extracted with ethyl acetate, the organiclayer was washed with saturated brine. The resultant mixture was driedover anhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and diisopropyl ether was added to the residue forcrystallization, and collected by filtration, to thereby obtain 615 mgof the title compound as the mixture of diastereomer compounds.

¹H-NMR(CDCl₃) δ: 1.24-2.32(19H, m), 3.30-3.45(1H, m), 3.59-3.81(1H, m),4.13-4.30(1H, m), 4.32-4.52(1H, m), 5.23-6.02(3H, m), 6.91-7.26(4H, m),7.41(1H, brs)

Step 2

Preparation of2-oxo-3-tert-butoxycarbonylamino-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 159 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-(2-cycloocten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(3-cyclopentenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.26-2.03(23H, m), 3.29(1H, dd), 3.32-3.46(1H, m),3.75(1H, dd), 4.38-4.49(1H, m), 5.51(1H, d), 6.90-6.96(2H, m),7.03-7.18(2H, m), 7.29(1H, s)

Step 3

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 3 of Example 159 was repeated except that2-oxo-3-tert-butoxycarbonylamino-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.26(9H, s), 1.31-2.03(23H, m), 3.21(1H, dd),3.31-3.42(1H, m), 3.65-3.74(1H, m), 4.12 (1H, d), 4.38-4.50(1H, m),5.14(1H, d), 5.56(1H, d), 6.92-7.19(4H, m)

Step 4

Preparation of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 158 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-cyclohexylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.21-2.00(25H, m), 3.15(1H, dd), 3.31-3.42(1H, m),3.49-3.67(2H, m), 4.01(1H, d), 5.27(1H, d), 6.91-7.19(4H, m)

Step 5

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Step 3 of Example 158 was repeated except that1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-cyclohexylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.22(9H, s), 1.25-2.03(23H, m), 3.13(1H, dd),3.33-3.45(1H, m), 3.76(1H, dd), 4.26(1H, d), 4.65-4.76(1H, m), 5.10(1H,d), 6.07(1H, d), 6.88(1H, s), 6.94-7.02(2H, m), 7.07-7.13(1H, m),7.15-7.22(1H, m), 7.24-7.32(1H, m), 7.56-7.65(2H, m), 7.78(1H, s)

Step 6

Preparation of3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 4 of Example 158 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclooctyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 215-217° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.18(9H, s), 1.30-1.98(14H, m), 3.14-3.40(2H, m),3.49-3.59(1H, m), 4.32-4.46(2H, m), 5.10(1H, d), 6.60(1H, d),6.97-7.19(3H, m), 7.20-7.37(2H, m), 7.43-7. 54(2H, m), 7.99(1H, s),9.04(1H, s), 12.80(1H, brs)

MS(FAB)m/z: 549(MH⁺)

IR(KBr)cm⁻¹:3357, 2926, 1719, 1690, 1655, 1595, 1557

Example 162

Preparation of5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]isophthalicacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrabydro-2H-1,5-benzodiazepin-3-yl)-3-[3,5-bis(metboxycarbonyl)phenyl]urea

Under ice-cooling, triphosgene (147 mg) was added to a solution ofdimethyl 5-aminoisophthalate (276 mg) in anhydrous tetrahydrofuran (30ml), triethylamine (0.59 ml) was added thereto five times over 15minutes after divided into five portions. After the mixture was stirredat room temperature for 5 minutes, a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(450 mg) in anhydrous tetrahydrofuran (10 ml) was added underice-cooling. The resultant mixture was stirred at room temperature forone hour, the reaction mixture was concentrated under reduced pressure.Water was added to the residue, crystals so precipitated were collectedby filtration and dried, to thereby obtain 700 mg of the title compound(Yield: 94%).

¹H-NMR(DMSO-d₆) δ: 1.10-1.82(18H, m), 1.95-2.05(1H, m), 3.16-3.35(2H,m), 3.41-3.48(1H, m), 3.86(6H, s), 4.33-4.46(2H, m), 5.13(1H, d),6.66(1H, d), 6.99-7.04(1H, m), 7.07 -7.14(1H, m), 7.23-7.32(2H, m),8.02(1H, t), 8.20(2H, d), 9.36(1H, s)

Step 2

Preparation of5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]isophthalicacid

Aqueous lithium hydroxide monohydrate (420 mg) solution (20 ml) wasadded to a solution of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-[3,5-bis(methoxycarbonyl)phenyl]urea(593 mg) in tetrahydrofuran (20 ml), the mixture was stirred at 50° C.for 2 hours. After allowed to cool, the reaction mixture wasconcentrated under reduced pressure, the residue was acidified with 1Nhydrochloric acid, extracted with the mixed solvent of chloroform andmethanol (5:1), and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, Isopropyl alcohol was added to theresidue, crystals so precipitated were collected by filtration, tothereby obtain 420 mg of the title compound (Yield: 74%).

¹H-NMR(DMSO-d₆) δ: 1.08-1.83(18H, m), 1.93-2.06(1H, m), 3.35-3.47(1H,m), 3.73-3.83(1H, m), 4.31-4.46(3H, m), 5.12(1H, d), 6.65(1H, d),6.99-7.05(1H, m), 7.06-7.14(1H, m), 7.21-7.32(2H, m), 8.02(1H, t),8.14(2H, d), 9.27(1H, s), 12.70(2H, brs)

MS(FAB)m/z: 565(MH⁺), 587(M+Na)⁺

IR(KBr)cm⁻¹:3347, 2936, 1717, 1692, 1649, 1609, 1561

Example 163

Preparation of2-methyl-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea

Under ice-cooling, triphosgene (205 mg) was added to a solution oftert-butyl 2-methyl-5-aminobenzoate (383 mg) in anhydroustetrahydrofuran (40 ml), triethylamine (825 μl) was added thereto fivetimes over 15 minutes after divided into five portions. After themixture was stirred at room temperature for 5 minutes, a solution of1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(600 mg) in anhydrous tetrahydrofuran (10 ml) was added underice-cooling. The resultant mixture was stirred at room temperature forone hour, the reaction mixture was poured into ice-water, extracted withethyl acetate, and the organic layer was washed with saturated brine.After dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure, diisopropyl ether was added to the residue forcrystallization, and collected by filtration, to thereby obtain 960 mgof the title compound (Yield: 97%).

¹H-NMR(DMSO-d₆) δ: 1.10-2.04(28H, m), 2.36(3H, s), 3.15-3.31(2H, m),3.42(1H, dd), 4.31-4.44(2H, m), 5.12(1H, d), 6.54(1H, d), 6.98-7.03(1H,m), 7.05-7.14(2H, m), 7.21-7.30(2H, m), 7.36(1H, dd), 7.70(1H, d),8.90(1H, s)

Step 2

Preparation of2-methyl-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 4 of Example 158 was repeated except that1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)ureawas used instead of1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Melting point: 222-224° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.09-1.82(18H, m), 1.94-2.05(1H, m), 2.40(3H, s),3.15-3.29(2H, m), 3.37-3.48(1H, m), 4.31-4.45(2H, m), 5.12(1H, d),6.54(1H, d), 6.98-7.15(3H, m), 7.21-7.37(3H, m), 7.84(1H, d), 8.89(1H,s), 12.71(1H, brs)

MS(FAB) 535(M+H), 557(M+Na)

IR(KBr)cm¹:3360, 2932, 1719, 1694, 1661, 1541, 1499

Example 164

Preparation of3-[3-(1-tert-butoxycarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea

Diphenylphosphoryl azide (938 mg) and triethylamine (354 mg) were addedto a solution of monobenzyl isophthalate (874 mg) in anhydroustetrahydrofuran (30 ml), the mixture was stirred at 100° C. for one hourand 30 minutes. The resultant mixture was allowed to cool,1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(680 mg) was added thereto, the mixture was stirred at room temperaturefor one hour. The reaction mixture was concentrated under reducedpressure, the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:3), to thereby obtain 890 mg of the titlecompound.

¹H-NMR(CDCl₃) δ: 1.04-2.03(10H, m), 3.14-3.25(1H, m)), 3.38(1H, dd),3.80(1H, dd), 4.75(1H, dt), 5.31(2H, s), 6.33(1H, d), 6.93-7.00(2H, m),7.13-7.21(2H, m), 7.28-7.41(6H, m), 7.63-7.67(1H, m), 7.87-7.92(2H, m),8.00-8.04(2H, m)

Step 2

Preparation of1-(1-tert-butoxycarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)ureaTert-butyl bromoacetate (503 mg), potassium iodide (23 ml), tetran-butylammonium bromide (23 mg) and potassium carbonate (713 mg) wereadded to a solution of1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea(800 mg) in dimethylsulfoxide (10 ml), the mixture was stirred at roomtemperature for one hour. Ice-water was added thereto, extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:2), to thereby obtain 970 mg of the titledcompound (Yield: 90%).

¹H-NMR(CDCl₃) δ: 1.05-2.04(19H, m), 3.11-3.23(1H, m), 3.38(1H, dd),3.61(1H, dd), 3.92(1H, d), 4.63(1H, d), 4.69-4.79(1H, m), 5.31(2H, s),6.42(1H, d), 7.02-7.42(11H, m), 7.63-7.69(2H, m), 7.90-7.94(1H, m)

Step 3

Preparation of3-[3-(1-tert-butoxycarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

5% Palladium carbon (300 mg) was added to a solution of1-(1-tert-butoxycarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea(960 mg) in ethanol (50 ml), the mixture was stirred at room temperaturefor 3 hours under hydrogen atmosphere. The reaction mixture wasfiltrated through a pad of Celite, and the filtrate was concentratedunder reduced pressure. Isopropyl alcohol was added to the residue forcrystallization, collected by filtrated, to thereby obtain 450 mg of thetitled compound.

Melting point: 187-189° C. (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.10-2.05(19H, m), 3.16-4.47(3H, m), 4.17(1H, d),4.31-4.43(1H, m), 4.51(1H, d), 6.63(1H, d), 7.10-7.37(5H, m),7.45-7.53(2H, m), 7.99(1H, t), 9.04(1H, s), 12.82(1H, brs)

MS(FAB)m/z: 537(MH′), 559(M+Na)⁺

IR(KBr)cm⁻¹:3360, 1738, 1692, 1649, 1545

Example 165

Preparation of(R)-(−)-3-[3-[1-(2-thenoyl)methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 1

Preparation of(R)-(+)-1-[1-(2-thenoyl)methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea

Step 7 of Example 143 was repeated except that 2-bromoacetylthiophenewas used instead of bromomethyl tert-butylketone, and thatN,N-dimethylacetamide was used as a solvent, to thereby obtain the titlecompound.

¹H-NMR(DMSO-d₆) δ: 1.10-1.82(9H, m), 1.52(9H, s), 1.95-2.07(1H, m),3.15-3.35(2H, m), 3.43(1H, dd), 4.43(1H, ddd), 4.94(1H, d), 5.48(1H, d),6.60(1H, d), 7.07-7.37(6H, m), 7.44(1H, dt), 7.54(1H, dq), 7.90(1H, t),8.08(1H, dd), 8.14(1H, dd), 9.04(1H, s)

[α] D (C=1.067, CHCl₃): +15.1°

Step 2

Preparation of(R)-(−)-3-[3-[1-(2-thenoyl)methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]ureido]benzoicacid

Step 4 of Example 133 was repeated except that(R)-(+)-1-[1-(2-thenoyl)methyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

Optical purity: 99.0% ee (the ee value was determined by HighPerformance Liquid Chromatography)

MS(FAB)m/z: 547(MH⁺), 136(base)

[α] D (C=1.01, CHCl₃): −14.1°

Example 166

Preparation of(R)-(−)-2-methyl-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea

Under ice-cooling, triphosgene (456 mg) was added to a solution oftert-butyl 2-methyl-5-aminobenzoate (850 mg) in anhydroustetrahydrofuran (50 ml), triethylamine (1.85 ml) was added thereto fivetimes each 0.37 ml over a 15 minutes after divided into five portions.After the mixture was stirred at room temperature for 5 minutes,(R)-(−)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(1.04 g) was added under ice-cooling. The resultant mixture was stirredat room temperature for one hour, the reaction mixture was poured intoice-water, and extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, crystals so precipitatedwere washed with diisopropyl ether, to thereby obtain 1.94 g of thetitle compound (Yield: 98%).

¹H-NMR(DMSO-d₆) δ: 1.10-2.03(19H, m), 2.37(3H, s), 3.16-3.35(2H, m),3.51(1H, dd), 4.25-4.36(1H, m), 6.53(1H, d), 6.96-7.02(2H, m),7.09-7.21(3H, m), 7.38(1H, dd), 7.72(1H, d), 8.93(1H, s), 9.83(1H, s)

[α] D²⁸ (C=1.15, DMSO): −133°

Step 2

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethy-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea

Step 7 of Example 143 was repeated except that(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)ureawas used instead of(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

[α] D²⁷ (C=1.08, CHCl₃): −64.1°

Step 3

Preparation of(R)-(−)-2-methyl-5-[3-(1-tert-butylcarbonylmethy-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Trifluoroacetic acid (10 ml) was added to(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea(1.9g) in methylene chloride (10 ml), the mixture was stirred at roomtemperature for one hour. The reaction mixture was concentrated underreduced pressure, the mixed solvent (100 ml) of diisopropyl ether andethanol (40:1) was added to the residue for crystallization, collectedby filtrated, to thereby obtain 1.47 g of the title compound (Yield:86%).

MS(FAB)m/z: 535(MH⁺), 557(M+Na)⁺

IR(KBr)cm⁻¹:3346, 2928, 2853, 1728, 1711, 1690, 1644, 1553, 1499

[α] D²³ (C=0.61, CHCl₃): −177°

Optical purity: 99.5% ee over (the ee value was determined by HighPerformance Liquid Chromatography)

Example 167

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of(3R)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclopenten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

In a similar manner to Step 1 of Example 159, by use of(R)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

Step 2

Preparation of(R)-(−)-²-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 2 of Example 159 was repeated except that(3R)-2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclopenten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclopenten-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

[α] D²⁵ (C=1.06, CHCl₃): −104°

Step 3

Preparation of(R)-(−)-2-oxo-3-amino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 5 of Example 143 was repeated except that(R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of(R)-(−)-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.19-1.34(1H, m), 1.50-2.05(9H, m), 3.22-3.39(2H, m),3.45-3.53(1H, m), 3.59-3.71(1H, m), 6.92-7.04(2H, m), 7.10-7.21(2H, m),7.29(1H, s)

[α] D²⁷ (C=1.09, CHCl₃): −59.3°

Step 4

Preparation of(R)-(−)-1-(2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Step 6 of Example 143 was repeated except that(R)-(−)-2-oxo-3-amino-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of(R)-(−)-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.07-1.20(1H, m), 1.35-2.05(16H, m), 3.21-3.43(2H,m), 3.59-3.74(1H, m), 4.19-4.31(1H, m), 6.59(1H, d), 6.97-7.08(2H, m),7.13-7. 25(2H, m), 7.32(1H, t), 7.43(1H, d), 7.54(1H, d), 7.91(1H, s),9.04(1H, s), 9.83(1H, s)

[α] D²⁶ (C=0.82, MeOH): −106°

Step 5

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea

Step 7 of Example 143 was repeated except that(R)-(−)-1-(2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

[α] D²⁵ (C=1.06, CHCl₃): −14.5°

Step 6

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 8 of Example 143 was repeated except that(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)ureawas used instead of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclopentyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

MS(FAB)m/z: 507(MH⁺), 529(M+Na)⁺

IR(KBr)cm⁻¹:3350, 2969, 2870, 1727, 1696, 1646, 1611, 1565, 1495

[α] D²⁶ (C=1.00, CHCl₃): −95.2°

Optical purity: 99% ee over (the ee value was determined by HighPerformance Liquid Chromatography)

Example 168

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 1

Preparation of(R)-(−)-(1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Step 3 of Example 121 was repeated except that a optical active compoundwas used instead of the racemic mixture, to thereby obtain the titlecompound.

[ a] D²³ (C=1.05, CHCl₃): −73.9°

Step 2

Preparation of(R)-(−)-(1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinehydrochloride(R)-(−)-(1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2 g) was suspended in ethanol (15 ml), 4N HCl-dioxane (10 ml) was addedto the suspension, and the mixture was stirred at 50° C. for one hour.After allowed to cool, crystals so precipitated were collected byfiltration, the crystals were washed with dioxane. The crystals weredried, to thereby obtain 1.6 g of the title compound (Yield: 93%).

[α] D²³ (C=1.12, MeOH): −10.4°

Step 3

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea

Step 3 of Example 15 was repeated except that(R)-(−)-(1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepinewas used instead of1-(N-phenyl-N-methyl)carbamoylmethyl-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.10-1.83(18H, m), 1.94-2.05(1H, m), 2.85(3H, s),3.17-3.47(3H, m), 4.32-4.46(2H, m), 5.12(1H, d), 6.52(1H, d),6.99-7.30(5H, m), 7.44-7.54(2H, m), 7.75(1H, t), 8.84(1H, s), 12.60(1H,brs)

MS(FAB) m/z : 636 (M+K)⁺ IR(KBr)cm⁻¹:2934, 1725, 1660, 1545

[α] D²⁵ (C=0.82, CHCl₃): −91.0°

Example 169

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylthioaceticacid

Step 1

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylthiophenyl)urea

Under ice-cooling, triphosgene (184 mg) was added to a solution of3-aminophenylthioacetic acid (395 mg) in anhydrous tetrahydrofuran (50ml), triethylamine (0. 75 ml) was added thereto five times each 0.15 mlover a 15 minutes after divided into five portions. After the mixturewas stirred at room temperature for 5 minutes, a solution of(R)-1-tert-butylcarbonylmathyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(570 mg) in tetrahydrofuran (10 ml) was added under ice-cooling, and theresultant mixture was stirred at room temperature for one hour. Waterwas added to the reaction mixture, and the resultant mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and purified bysilica gel column chromatography (n-hexane:ethyl acetate=2:1), tothereby obtain 1 g of the title compound.

¹H-NMR(CDCl₃) δ: 1.12-1.89(27H, m), 1.97-2.08(1H, m), 3.16-3.27 (1H, m),3.37(1H, dd), 3.53 (2H, s), 3.63( (1H, dd), 4.23 (1H, d), 4.66-4.77 (1H,m) ,5.14 (1H, d), 6.30(1H, d), 6.94-7.13 (6H, m), 7.17-7.21 (2H, m),7.42(1H, t)

[α] D²⁴ (C=1.04, CHCl₃): −56.0°

Step 2

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylthioaceticacid

Step 8 of Example 143 was repeated except that(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-³-(3-tert-butoxycarbonylmethylthiophenyl)ureawas used instead of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound as amorphous.

¹H-NMR(DMSO-d₆) δ: 1.10-1.82(18H, m), 1.92-2.02(1H, m), 3.15-3.45(3H,m), 3.49(2H, s), 4.31-4.43(2H, m), 5.11(1H, d), 6.74-6.82(2H, m),6.98-7.13(4H, m), 7.20-7.34(3H, m), 9.05(1H, s), 12.50(1H, brs)

MS(FAB)m/z: 605(M+K)⁺

IR(KBr)cm⁻¹:3370, 2932, 1725, 1655, 1593

[α] D²³ (C=1.00, CHCl₃): −29.7°

Example 170

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl-ureido]phenylaceticacid

Step 1

Preparation of(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)urea

Step 6 of Example 143 was repeated except that tert-butyl3-aminophenylacetate was used instead of tert-butyl 3-aminobenzoate, tothereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.05-1.89(18H, m), 1.97-2.09(1H, m), 3.17-3.28(1H, m),3.40(1H, dd), 3.47(2H, s), 3.85(1H, dd), 4.73(1H, dt), 6.33(1H, d),6.82-7.06(3H, m), 7.13-7.28(4H, m), 7.49-7.54(1H, m), 8.07(2H, s)

[α] D²¹ (C=1.05, CHCl₃): −171°

Step 2

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)urea

(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)urea(4.93 g) was added to a suspension of 60% sodium hydride (440 mg) inanhydrous N,N-dimethylformamide (50 ml) under ice-cooling, the mixturewas stirred for one hour. Bromomethyl tert-butylketone (1.97 g) wasadded thereto, the resultant mixture was stirred at room temperature forone hour, the reaction mixture was poured into ice-water, extracted withethyl acetate, and the organic layer was washed with saturated brine.After dried over anhydrous sodium sulfate, the mixture was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:3), tothereby obtain 5.07 g of the title compound (Yield: 86%).

¹H-NMR(CDCl₃) δ: 1.06-1.89(27H, m), 1.97-2.09(1H, m), 3.15-3.27(1H, m),3.34(1H, dd), 3.43(2H, s), 3.66(1H, dd), 4.23(1H, d), 4.70(1H, dt),5.12(1H, d) 6.14(1H, d), 6.83(1H, s), 6.86-6.92(1H, m), 6.95-7.04(2H,m), 7.07-7.24(5H, m)

[α] D²⁴ (C=1.03, CHCl₃): −62.3°

Step 3

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]phenylaceticacid

Step 8 of Example 143 was repeated except that(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)ureawas used instead of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.05-1.81(18H, m), 1.91-2.02(1H, m), 3.13-3.42(5H,m), 4.31-4.43(2H, m), 5.11(1H, d), 6.69(1H, d), 6.78(1H, d),6.98-7.28(7H, m), 8.92(1H, s), 12.50(1H, brs)

MS(FAB)m/z: 535(MH⁺), 557(M+Na)⁺, 573(M+K)⁺

IR(KBr)cm⁻¹:3370, 2932, 1725, 1655, 1559

[α] D²⁴ (C=1.05, MeOH): −64.6°

Example 171

Preparation of(R)-(−)-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]-2-methylbenzoicacid

Step 1

Preparation of(3R)-(−)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

Nitrobenzene (22.16 g) and 10% palladium carbon (6 g) were added to asolution of(3R)-2-oxo-3-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(12.87 g) in xylene (200 ml), the mixture was refluxed for one hour and30 minutes. The reaction mixture was allowed to cool, filtered, and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in ethanol (30 ml), 4N HCl-dioxane (20 ml) was added, theresultant mixture was stirred at 50° C. for one hour. After allowed tocool, crystals so precipitated were collected by filtration, thecrystals were washed with 2-propanol, to thereby obtain hydrochloride ofthe title compound. The compound was dissolved under heating in themixed solvent of methanol and water, allowed to cool, saturated sodiumbicarbonate was added for neutralization, crystals so precipitated werecollected be filtration, the crystals were washed with water and dried,to thereby obtain 5.55 g of the title compound (Yield: 86%).

¹H-NMR(DMSO-d₆) δ: 1.83(2H, brs), 3.41-3.53(2H, m), 3.89(1H, ABq),6.62-6.68(2H, m), 6.74-6.81(1H, m), 7.08-7.25(6H, m), 9.87(1H, s)

[α] D²³ (C=1.00, DMSO): −66.0°

Step 2

Preparation of(R)-(−)-1-(2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea

Step 6 of Example 143 was repeated except that tert-butyl5-amino-2-methylbenzoate was used instead of tert-butyl 3-aminobenzoate,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.52(9H, s), 2.37(3H, s), 3.64(1H, dd), 4.08(1H, dd),4.46-4.57(1H, m), 6.62(1H, d), 6.66-6.84(3H, m), 7.10-7.42(8H, m),7.75(1H, d), 9.01(1H, s), 10.14(1H, s)

[α] D²² (C=1.00, CHCl₃): −192°

Step 3

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)urea

Step 2 of Example 170 was repeated except that(R)-(−)-1-(2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)ureawas used instead of(R)-(−)-1-(2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylmethylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.23(9H, s), 1.57(9H, s), 2.47(3H, s), 3.65(1H, dd),4.24(1H, dd), 4.42(1H, d), 4.84-4.95(1H, m), 5.13(1H, d), 6.14(1H, d),6.76-6.89(4H, m), 7.05-7.25(7H, m), 7.37(1H, dd), 7.67(1H, d)

[α] D²³ (C=0.72, CHCl₃): −111°

Step 4

Preparation of(R)-(−)-5-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]-2-methylbenzoicacid

Step 8 of Example 143 was repeated except that(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonyl-4-methylphenyl)ureawas used instead of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea,to thereby obtain the title compound.

¹H-NMR(DMSO-d₆) δ: 1.17(9H, s), 2.41(3H, s), 3.54-3.63(1H, m), 4.01(1H,dd), 4.52-4.63(1H, m), 4.74(1H, d), 5.12(1H, d), 6.65(1H, d),6.67-6.89(3H, m), 7.11-7.41(8H, m), 7.88(1H, d), 8.97(1H, s), 12.70(1H,brs)

MS(FAB)m/z: 529(MH⁺)

[a] D²² (C=0.67, CHCl₃): −269°

The structure of these compounds obtained from Example 122-171 was shownin Table 18-24, except for the Examples for producing salt only.

TABLE 18

Example R₁ R₂ R₃ R_(p) n 122 8-CH₃

1 123 H

1 124 H

1 125 (*) H

1 126 (*) 8-CH₃

1 131 H

1 (*): optically active compound

TABLE 19

Example R₁ R₂ R₃ R_(p) n 132 H

1 133 H

1 134 H

1 135 8-CH₃

1 136 8-CH₃

1 137 8-CH₃

1

TABLE 20

Example R₁ R₂ R₃ R_(p) n 138 8-CH₃

1 139 8-CH₃

1 140 (*) 8-CH₃

1 141 (*) 8-CH₃

1 142 (*) 8-CH₃

1 143 (*) H

1 (*): optically active compound

TABLE 21

Example R₁ R₂ R₃ R_(p) n 144 H

1 145 H

1 146 H

1 147 H

1 148 H

1 149 H

1 150 H

1

TABLE 22

Example R₁ R₂ R₃ R_(p) n 151 H

1 152 H

1 153 H

1 154 H

1 155 H

1 156 H

1 157 H

1

TABLE 23

Example R₁ R₂ R₃ R_(p) n 158 H

1 159 H

1 160 H

1 161 H

1 162 H

1 163 H

1 164 H

1

TABLE 24

Example R₁ R₂ R₃ R_(p) n 165 (*) H

1 166 (*) H

1 167 (*) H

1 168 (*) H

1 169 (*) H

1 170 (*) H

1 171 (*) H

1 (*): optically active compound

Example 172

Preparation of(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid (R)-(+)-α-methylbenzylamine salt

(R)-(+)-α-methylbenzylamine (242 mg) was added to a solution of(±)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid (1.03 g) in 2-propanol (20 ml), the mixture was stirred overnight.Crystals so precipitated were collected by filtration, the crystals wererecrystallized from 2-propanol, to thereby obtain 220 mg of the titlecompound.

Optical purity: 99.7%ee over (After the compound was converted into freebase, the ee value was determined by High Performance LiquidChromatography)

Example 173

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

Step 1

Preparation of(R)-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine

(R)-2-oxo-3-(N-tert-butoxycarbonyl)amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(3.50 g) was dissolved in 4N HCl-dioxane (23.4 ml), stirred at 60° C.for one hour. After the reaction mixture was concentrated under reducedpressure, methylene chloride and saturated aqueous sodium bicarbonatewere added to the residue, and extracted. The organic layer wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, tothereby obtain 2.20 g of the title compound as amorphous (Yield: 85.9%).

¹H-NMR(DMSO-d₆) δ: 1.12-1.94(10H, m), 2.24(1H, s), 3.19-3.77(4H, m),6.83(1H, s), 6.96(1H, d), 7.12(1H, d), 10.12(1H, s)

Step 2

Preparation of(R)-1-(2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea

Tert-butyl 3-aminobenzoate (1.63 g) was dissolved in tetrahydrofuran (30ml), the solution was cooled to internal temperature 5-8° C. Triphosgene(0.91 g) was added to the solution, stirred for 5 minutes. Subsequentlytriethylamine (4.30 ml) was added thereto four times after divided intofour portions. After the mixture was stirred at room temperature for 10minutes, a solution of(R)-2-oxo-3-amino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine(2.10 g) in tetrahydrofuran (10 ml) was added, the resultant mixture wasstirred for one hour. Water and ethyl acetate were added the reactionmixture, and extracted. The organic layer was successively washed withwater and saturated brine, dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, to thereby obtain 3.28 gof the title compound as amorphous (Yield: 86.8%).

¹H-NMR(DMSO-d₆) δ: 1.18-1.99(19H, m), 2.24(3H, s), 3.20-3.49(3H, m),4.26-4.31 (1H, m), 6.57(1H, d), 6.81(1H, s), 6.96(1H, d), 7.09(1H, d),7.32(1H, t), 7.44(1H, d), 7.54(1H, d), 7.92(1H, s), 9.06(1H, s),9.78(1H, s)

Step 3

Preparation of(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea

(R)-1-(2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea(500 mg) was dissolved in N,N-dimethylformamide (5 ml), the solution wascooled to internal temperature 5° C. Under argon atmosphere, 60% sodiumhydride (49 mg) was added, the mixture was stirred at internaltemperature 5° C. for 30 minutes. Bromomethyl tert-butylketone (218 mg)was added thereto, stirred at internal temperature 5° C. for one hour.The reaction mixture was poured into ice-water, extracted with ethylacetate. The organic layer was successively washed with water andsaturated brine, dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (chloroform), to thereby obtain 200 mg of thetitle compound.

¹H-NMR(DMSO-d₆) δ: 0.83-1.99(28H, m), 2.27(3H, s), 3.16-3.31(3H, m),4.34-4.40(2H, m), 5.10(1H, d), 6.58(1H, d), 6.83(1H, s), 7.06(1H, d),7.17(1H, d), 7.32(1H, t), 7.43(1H, d), 7.53(1H, d), 7.90(1H, s),9.03(1H, s)

[α] D²² (C=1.3, CHCl₃): −27.0°

Step 4

Preparation of(R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)ureido]benzoicacid

(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea(100 mg) was dissolved in methylene chloride (1 ml), trifluoroaceticacid (1 ml) was added, the mixture was stirred at room temperature for30 minutes. After the solvent was evaporated, isopropyl ether was addedto the residue, powder so precipitated was collected by filtration, tothereby obtain 50 mg of the title compound.

[α] D²⁷ (C=0.26, CHCl₃): −64.0°

Test 1

Measurement of Binding Affinity for CCK-B Receptors

Cerebral cortices were removed from Hartley-strain guinea pigs, thecerebral cortices were homogenized in 50 volumes of 50 mM Tris-HClbuffer (pH7.4) and centrifuged at 50000×g for 10 minutes. The Tris-HClbuffer was added to the pellet and recentrifuged as above two times. Thefinal pellet was rehomogenized in 10 mM HEPES buffer (pH 6.5, whichhereinafter be abbreviated as “solvent”) containing 5 mM MgCl₂, 1 mMEGTA, 0.25 mg/ml bacitracin and 130 mM NaCl, and used as the receptorpreparation.

Binding assay was measured as follows. Fifty μl of [³H]CCK-8 (at thefinal concentration of 1.0 nM) and 900 μl of the receptor preparation(800 μg protein/tube) were added to 50 μl of either solvent, CCK-8 (1μM) or a test compound. These ware reacted at 25° C. for 2 hours. Afterthe reaction, the mixture was filtrated through Whatman GF/B filterpresoaked in 0.1% BSA. The filter was washed with 3 ml of ice-cold 50 mMTris-HCl buffer (pH 7.4) four times, immediately after the filtration.The filter was soaked in the ACS-II scintillation cocktail for a day andradioactivity was measured using a liquid scintillation counter.Non-specific binding was defined as the radioactivity in the presence of1 μM CCK-8. Specific binding was defined as the difference between totalbinding (used solvent without CCK-8) and non-specific binding. Inhibitordissociation constant (Ki) of each test compound was determined from theinhibition of specific [³H]CCK-8 binding.

Results are shown in Tables 25 and 26.

TABLE 25 Measurement of binding affinity for CCK-B receptors Testcompound Ki (nM) Compound of Example 1 6.47 Compound of Example 4 1.11Compound of Example 10 6.87 Compound of Example 13 (racemate) 3.16Compound of Example 13 (+form) 1.16 Compound of Example 15 0.99 Compoundof Example 16 2.14 Compound of Example 33 0.14 Compound of Example 350.61 Compound of Example 46 0.70 Compound of Example 49 5.02 Compound ofExample 56 1.42 Compound of Example 61 0.98 Compound of Example 62 0.79Compound of Example 70 (recemate) 0.77 Compound of Example 70 (−form)0.36 Compound of Example 71 2.88 Compound of Example 72 1.57 Compound ofExample 78 0.18 Compound of Example 80 2.62 Compound of Example 81 0.56Compound of Example 87 1.39 Compound of Example 88 (−form) 0.11

TABLE 26 Measurement of binding affinity for CCK-B receptors Testcompound Ki (nM) Compound of Example 93 1.29 Compound of Example 94 1.62Compound of Example 95 2.26 Compound of Example 97 1.59 Compound ofExample 101 1.13 Compound of Example 104 0.59 Compound of Example 1051.33 Compound of Example 109 1.81 Compound of Example 114 9.43 Compoundof Example 120 0.75 Compound of Example 121 1.20 Compound of Example 1250.43 Compound of Example 143 0.63 Compound of Example 151 2.86 Compoundof Example 157 1.97 Compound of Example 168 0.21 Compound of Example 1690.1 L-365, 260 24.6

Measurement of Inhibition of Pentagastrin-stimulated Acid Secretion

Male Sprague-Dawley (SD)-strain rats were used. Each rat was operated toligate the pylorus, and equip with a duodenal catheter and gastricfistula under a ether anesthesia. After the operation, each rat wasplaced in a Bollman-type cage and continuously infused pentagastrin (15μg/kg/hr) through the tail vein. Test compounds were suspended in 0.5%aqueous sodium carboxymethylcellulose (which hereinafter be abbreviatedas “vehicle”). Vehicle or test compound was administered through theintraduodenal catheter 1 hour after the beginning of pentagastrininfusion. Acidity of the collected gastric juice was measured by anautomatic titillation device. Acid output was determined by multiplyingthe volume by the acidity of gastric juice. Percent inhibition of acidoutput from 1 to 4 hours after administration of test compound wascalculated by the following equation.${\% \quad {inhibition}} = {\frac{\begin{matrix}\left( {{{mean}\quad {acid}\quad {output}\quad {of}\quad {vehicle}\quad {treated}\quad {group}} -} \right. \\\left. {{mean}\quad {acid}\quad {output}\quad {of}\quad {test}\quad {compound}\quad {treated}\quad {group}} \right)\end{matrix}}{\text{Mean acid output of vehicle treated group}} \times 100}$

Results are presented in Table 27.

TABLE 27 Measurement of inhibition of pentagastrin-stimulated acidsecretion Test compound Dose (mg/kg) % Inhibition Compound of Example 130 59.4 Compound of Example 10 10 67.1 Compound of Example 13 (racemate)3 80.9 Compound of Example 13 (+form) 1 81.5 Compound of Example 33 377.2 Compound of Example 56 10 69.8 Compound of Example 70 (racemate) 376.5 Compound of Example 70 (−form) 1 84.8 Compound of Example 80 3 45.4Compound of Example 87 30 80.1 Compound of Example 88 (−form) 1 68.4Compound of Example 89 30 87.8 Compound of Example 94 30 93.3 Compoundof Example 95 1 49.0 Compound of Example 101 3 78.0 Compound of Example104 1 58.0 Compound of Example 109 1 54.0 Compound of Example 113 3075.7 Compound of Example 114 30 89.7 Compound of Example 118 30 88.3Compound of Example 120 30 88.3 Compound of Example 121 0.3 47.0Compound of Example 143 0.1 54.6 Compound of Example 166 0.3 51.2Compound of Example 168 1 58.9 Compound of Example 169 1 75.2 L-365, 26030 46.5

Test 3

Measurement of Binding Affinity for CCK-A Receptors

Pancreases were removed from Hartley-strain guinea pigs, the pancreaseswere homogenized in 40 volumes of 10 mM PIPES buffer (pH 6.5, whichhereinafter be abbreviated as “solvent”) containing 1 mM EGTA, 30 mMMgCl₂, 0.02% bacitracin, 0.02% soybean trypsin inhibitor and 0.3 Msucrose. The homogenate was filtrated through gauze and centrifuged at50000×g for 10 minutes. Solvent was added to the pellet andrecentrifuged as above. The final pellet thus obtained was homogenizedin 40 volumes of solvent and used as the receptor preparation.

Binding assay was measured as follows. Fifty μl of [³H]L-364, 718 (atthe final concentration of 0.2 nM) and 900 μl of the receptorpreparation (50 μg protein/tube) were added to 50 μl of solvent, orL-364, 718 (1 μM) or a test compound. This mixture was incubated at 25°C. for 2 hours. After the reaction, the mixture was filtrated throughWhatman GF/B filter presoaked in 0.1% BSA (bovine serum albumin). Thefilter was washed with 3 ml of ice-cold 10 mM PIPES buffer (pH 6.5)three times, immediately after the filtration. The filter was soaked inthe ACS-II scintillation cocktail for one day and radioactivity wasmeasured using a liquid scintillation counter. Non-specific binding wasdefined as the radioactivity in the presence of 1 μM L-364, 718.Specific binding was defined as the difference between total binding(used solvent without L-364, 718) and non-specific binding. lnhibitordissociation constant (Ki) of each test compound was determined from theinhibition of specific [³H]L-364, 718 binding.

Results are shown in Table 28.

TABLE 28 Measurement of Binding Affinity for CCK-A Receptors Testcompound Ki (nM) Compound of Example 14 13.2 Compound of Example 28 14.3Compound of Example 33 244 Compound of Example 70 (racemate) 303Compound of Example 70 (−form) 255 Compound of Example 87 120 Compoundof Example 88 (-form) 16.7 Compound of Example 97 367 Compound ofExample 101 472 Compound of Example 104 130 Compound of Example 109 346Compound of Example 111 6.34 Compound of Example 120 506 L-365, 260 0.64

Test 4

Toxicity Test

Three male Sprague-Dawley (SD)-strain rats (5.5 weeks) were employed.Test compound suspended in aqueous 0.5% methylcellulose was orallyadministered at a dose of 1000 mg/kg. No case of death was observed ineach group until one week after the administration.

Formulation Example 1 Compound of Example 1 20 g Lactose 315 g CornStarch 125 g Crystalline cellulose 25 g

The above-described ingredients were uniformly mixed, followed by theaddition of 200 ml of a 7.5% aqueous hydroxypropylcellulose solution.The mixture was pulverized into granules through a screen of 0.5 mm indiameter by an extruder. Immediately after that, the resultant granuleswere rounded by Marumerizer and then dried, whereby granules wereobtained.

Formulation Example 2 Compound of Example 15 20 g Lactose 100 g CornStarch 36 g Crystalline cellulose 30 g Carboxymethycellulose calcium 10g Magnesium stearate 4 g

The above-described ingredients were uniformly mixed. The mixture waspressed into 200 mg tablets by a punch of 7.5 mm in diameter on a singlepunch tableting machine.

Formulation Example 3 Compound of Example 54 100 mg Sodium acetate 2 mgAcetic acid (for adjusting pH to 5.8) q.s. Distilled water q.s. Total 10ml/vial

Accordingly to the above formulation, an injection was prepared in amanner known per se in the art.

Formulation Example 4 Compound of Example 89 20 g Lactose 315 g CornStarch 125 g Crystalline cellulose 25 g

The above-described ingredients were uniformly mixed, followed by theaddition of 200 ml of a 7.5% aqueous hydroxypropylcellulose solution.The mixture was pulverized into granules through a screen of 0.5 mm indiameter by an extruder. Immediately after that, the resultant granuleswere rounded by Marumerizer and then dried, whereby granules wereobtained.

Formulation Example 5 Compound of Example 93 20 g Lactose 100 g CornStarch 36 g Crystalline cellulose 30 g Carboxymethycellulose calcium 10g Magnesium stearate 4 g

The above-described ingredients were uniformly mixed. The mixture waspressed into 200 mg tablets by a punch of 7.5 mm in diameter on a singlepunch tableting machine.

Formulation Example 6 Compound of Example 98 100 mg Sodium acetate 2 mgAcetic acid (for adjusting pH to 5.8) q.s. Distilled water q.s. Total 10ml/vial

Accordingly to the above formulation, an injection was prepared in amanner known per se in the art.

CAPABILITY OF EXPLOITATION IN INDUSTRY

The compounds of the present invention exhibit excellent gastrin and/orCCK-B receptor antagonism as well as strong action of suppressingsecretion dog gastric acid, and exhibit high safety. Therefore thecompounds of the present invention are used widely in the medical field,that include gastric ulcer, duodenal ulcer, gastritis, refluxesophagitis, pancreatitis, Zolinger-Ellison syndrome, vacuolating G-cellhyperplasia, basal-mucous-membrane hyperplasia, inflammation of thegallbladder, attack of biliary colic, motor disorders of alimentarycanal, irritable bowel syndrome, certain types of tumors, eatingdisorders, anxiety, panic disorder, depression, schizophrenia,Parkinson's disease, tardive dyskinesia, Gilles de la Tourette syndrome,drug dependence, and drug-withdrawal symptoms;and drug-withdrawalsymptoms; and induction of pain relief or facilitation of induction ofpain relief by use of an opioid drug.

What is claimed is:
 1. A compound represented by the following formula(I) or a salt thereof:

wherein R₁ represents a hydrogen atom, a lower alkyl group, a loweralkoxyl group, or a halogen atom; each of R₂ and R₃, which may be thesame or different, represents a hydrogen atom, a lower alkenyl group, alower alkyl group which may be substituted by a halogen atom, a loweralkylsulfonyl group, a mono- or di-lower alkoxyalkyl group, a phenylgroup which may have a substituent, a group represented by —CH(R₆)R₇(wherein R₆ represents a lower alkyl group, a lower alkoxyl group, amono- or di-lower alkoxyalkyl group, a saturated or unsaturatedhydrocarbon group having a bicyclic or tricyclic C7-C10 condensed ring,or a phenyl or heterocyclic group which may have a substituent; and R₇represents a hydrogen atom or a lower alkyl group), or a grouprepresented by —CO—R₈ (wherein R₈ represents a lower alkyl group whichmay be substituted by a halogen atom; a lower alkenyl group; a loweralkoxyl group; a mono- or di-lower alkoxyalkyl group; an adamantylgroup; a hydroxyl group; a benzyloxy group; a phenyl or heterocyclicgroup which may have a substituent; or a group represented by —N(R₉)R₁₀(wherein R₉ and R₁₀ may be the same or different, and each represents ahydrogen atom, a lower alkyl group, a hydroxyalkyl group, a mono- ordi-lower alkylaminoalkyl group, a phenyl group, or a heterocyclic groupwhich may have a substituent)); each of R₄ and R₅, which may beidentical to or different from each other, represents a hydrogen atom, alower alkyl group which may be substituted by a halogen atom, a loweralkoxyl group, a halogen atom, a hydroxyalkyl group, an amino group, anitro group, a mono- or di-lower alkylamino group, a loweralkylsulfonylaminocarbonyl group, a hydroxyaminocarbonyl group, abenzyloxyaminocarbonyl group, a tetrazolyl group, a 4-oxoxadiazolinylgroup, a group represented by the following formula:

 (wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R₁₁ represents ahydrogen atom, a lower alkyl group or a benzyl group); Ar represents abenzene or naphthalene ring, or an aromatic heterocyclic ring; and nrepresents an integer between 0 and 2 inclusive, wherein saidheterocyclic group independently is selected from 5 and 6 membered ringscontaining at least one heteroatom selected from the group consisting ofN, O and S; wherein said substituent independently is selected from oneor two substituents selected from the group consisting of a lower alkylgroup, a lower alkoxy group, a halogen atom, an amino group and a nitrogroup; and wherein at least one of R₂, R₃, R₄ and R₅ contains a carbonylgroup.
 2. The compound according to claim 1, wherein R₂ is a group—COR₈.
 3. The compound according to claim 1, wherein Ar is a benzenering, and at least one of R₄ and R₅ is a group —Y—COOR₁₁.
 4. Thecompound according to claim 2, wherein Ar is a benzene ring, and atleast one of R₄ and R₅ is a group —Y—COOR₁₁.
 5. A compound representedby the following formula (I) or a salt thereof:

wherein R¹ represents a hydrogen atom, a lower alkyl group, a loweralkoxyl group, or a halogen atom; R₂ represents —CO—R₈; R₃ represents ahydrogen atom, a lower alkenyl group, a lower alkyl group which may besubstituted by a halogen atom, a lower alkylsulfonyl group, a mono- ordi-lower alkoxyalkyl group, a phenyl group which may have a substituent,a group represented by —CH(R₆)R₇ (wherein R₆ represents a lower alkylgroup, a lower alkoxyl group, a mono- or di-lower alkoxyalkyl group, asaturated or unsaturated hydrocarbon group having a bicyclic ortricyclic C7-C10 condensed ring, or a phenyl or heterocyclic group whichmay have a substituent; and R₇ represents a hydrogen atom or a loweralkyl group), or a group represented by —CO—R₈ (wherein R₈ represents alower alkyl group which may be substituted by a halogen atom; a loweralkenyl group; a lower alkoxyl group; a mono- or di-lower alkoxyalkylgroup; an adamantyl group; a hydroxyl group; a benzyloxy group; a phenylor heterocyclic group which may have a substituent; or a grouprepresented by —N(R₉)R₁₀ (wherein R₉ and R₁₀ may be the same ordifferent, and each represents a hydrogen atom, a lower alkyl group, ahydroxyalkyl group, a mono- or di-lower alkylaminoalkyl group, a phenylgroup, or a heterocyclic group which may have a substituent)); each ofR₄ and R₅, which may be identical to or different from each other,represents a hydrogen atom, a lower alkyl group which may be substitutedby a halogen atom, a lower alkoxyl group, a halogen atom, a hydroxyalkylgroup, an amino group, a nitro group, a mono- or di-lower alkylaminogroup, a lower alkylsulfonylaminocarbonyl group, a hydroxyaminocarbonylgroup, a benzyloxyaminocarbonyl group, a tetrazolyl group, a4-oxoxadiazolinyl group, a group represented by the following formula:

 (wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R₁₁ represents ahydrogen atom, a lower alkyl group or a benzyl group); Ar represents abenzene or naphthalene ring, or an aromatic heterocyclic ring; and nrepresents an integer between 0 and 2 inclusive, wherein saidheterocyclic group independently is selected from 5 and 6 membered ringscontaining at least one heteroatom selected from the group consisting ofN, O and S; and wherein said substituent independently is selected fromone or two substituents selected from the group consisting of a loweralkyl group, a lower alkoxy group, a halogen atom, an amino group and anitro group.
 6. A compound represented by the following formula (I) or asalt thereof:

wherein R₁ represents a hydrogen atom, a lower alkyl group, a loweralkoxyl group, or a halogen atom; R₂ represents a hydrogen atom, a loweralkenyl group, a lower alkyl group which may be substituted by a halogenatom, a lower alkylsulfonyl group, a mono- or di-lower alkoxyalkylgroup, a phenyl group which may have a substituent, a group representedby —CH(R₆)R₇ (wherein R₆ represents a lower alkyl group, a lower alkoxylgroup, a mono- or di-lower alkoxyalkyl group, a saturated or unsaturatedhydrocarbon group having a bicyclic or tricyclic C7-C10 condensed ring,or a phenyl or heterocyclic group which may have a substituent; and R₇represents a hydrogen atom or a lower alkyl group), or a grouprepresented by —CO—R₈ (wherein R₈ represents a lower alkyl group whichmay be substituted by a halogen atom; a lower alkenyl group; a loweralkoxyl group; a mono- or di-lower alkoxyalkyl group; an adamantylgroup; a hydroxyl group; a benzyloxy group; a phenyl or heterocyclicgroup which may have a substituent; or a group represented by —N(R₉)R₁₀(wherein R₉ and R₁₀ may be the same or different, and each represents ahydrogen atom, a lower alkyl group, a hydroxyalkyl group, a mono- ordi-lower alkylaminoalkyl group, a phenyl group, or a heterocyclic groupwhich may have a substituent)); R₃ represents —CO—R₈; each of R₄ and R₅,which may be identical to or different from each other, represents ahydrogen atom, a lower alkyl group which may be substituted by a halogenatom, a lower alkoxyl group, a halogen atom, a hydroxyalkyl group, anamino group, a nitro group, a mono- or di-lower alkylamino group, alower alkylsulfonylaminocarbonyl group, a hydroxyaminocarbonyl group, abenzyloxyaminocarbonyl group, a tetrazolyl group, a 4-oxoxadiazolinylgroup, a group represented by the following formula:

 (wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R₁₁ represents ahydrogen atom, a lower alkyl group or a benzyl group); Ar represents abenzene or naphthalene ring, or an aromatic heterocyclic ring; and nrepresents an integer between 0 and 2 inclusive, wherein saidheterocyclic group independently is selected from 5 and 6 membered ringscontaining at least one heteroatom selected from the group consisting ofN, O and S; and wherein said substituent independently is selected fromone or two substituents selected from the group consisting of a loweralkyl group, a lower alkoxy group, a halogen atom, an amino group and anitro group.
 7. A compound represented by the following formula (I) or asalt thereof:

wherein R₁ represents a hydrogen atom, a lower alkyl group, a loweralkoxyl group, or a halogen atom; each of R₂ and R₃, which may be thesame or different, represents a hydrogen atom, a lower alkenyl group, alower alkyl group which may be substituted by a halogen atom, a loweralkylsulfonyl group, a mono- or di-lower alkoxyalkyl group, a phenylgroup which may have a substituent, a group represented by —CH(R₆)R₇(wherein R₆ represents a lower alkyl group, a lower alkoxyl group, amono- or di-lower alkoxyalkyl group, a saturated or unsaturatedhydrocarbon group having a bicyclic or tricyclic C7-C10 condensed ring,or a phenyl or heterocyclic group which may have a substituent; and R₇represents a hydrogen atom or a lower alkyl group), or a grouprepresented by —CO—R₈ (wherein R₈ represents a lower alkyl group whichmay be substituted by a halogen atom; a lower alkenyl group; a loweralkoxyl group; a mono- or di-lower alkoxyalkyl group; an adamantylgroup; a hydroxyl group; a benzyloxy group; a phenyl or heterocyclicgroup which may have a substituent; or a group represented by —N(R₉)R₁₀(wherein R₉ and R₁₀ may be the same or different, and each represents ahydrogen atom, a lower alkyl group, a hydroxyalkyl group, a mono- ordi-lower alkylaminoalkyl group, a phenyl group, or a heterocyclic groupwhich may have a substituent)); R₄ represents a loweralkylsulfonylaminocarbonyl group, a hydroxyaminocarbonyl group, abenzyloxyaminocarbonyl group, a group represented by the followingformula:

 (wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R₁₁ represents ahydrogen atom, a lower alkyl group or a benzyl group); R₅ represents ahydrogen atom, a lower alkyl group which may be substituted by a halogenatom, a lower alkoxyl group, a halogen atom, a hydroxyalkyl group, anamino group, a nitro group, a mono- or di-lower alkylamino group, alower alkylsulfonylaminocarbonyl group, a hydroxyaminocarbonyl group, abenzyloxyaminocarbonyl group, a tetrazolyl group, a 4-oxoxadiazolinylgroup, a group represented by the following formula:

 (wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R₁₁ represents ahydrogen atom, a lower alkyl group or a benzyl group); Ar represents abenzene or naphthalene ring, or an aromatic heterocyclic ring; and nrepresents an integer between 0 and 2 inclusive, wherein saidheterocyclic group independently is selected from 5 and 6 membered ringscontaining at least one heteroatom selected from the group consisting ofN, O and S; and wherein said substituent independently is selected fromone or two substituents selected from the group consisting of a loweralkyl group, a lower alkoxy group, a halogen atom, an amino group and anitro group.
 8. A compound represented by the following formula (I) or asalt thereof:

wherein R₁ represents a hydrogen atom, a lower alkyl group, a loweralkoxyl group, or a halogen atom; each of R₂ and R₃, which may be thesame or different, represents a hydrogen atom, a lower alkenyl group, alower alkyl group which may be substituted by a halogen atom, a loweralkylsulfonyl group, a mono- or di-lower alkoxyalkyl group, a phenylgroup which may have a substituent, a group represented by —CH(R₆)R₇(wherein R₆ represents a lower alkyl group, a lower alkoxyl group, amono- or di-lower alkoxyalkyl group, a saturated or unsaturatedhydrocarbon group having a bicyclic or tricyclic C7-C10 condensed ring,or a phenyl or heterocyclic group which may have a substituent; and R₇represents a hydrogen atom or a lower alkyl group), or a grouprepresented by —CO—R₈ (wherein R₈ represents a lower alkyl group whichmay be substituted by a halogen atom; a lower alkenyl group; a loweralkoxyl group; a mono- or di-lower alkoxyalkyl group; an adamantylgroup; a hydroxyl group; a benzyloxy group; a phenyl or heterocyclicgroup which may have a substituent; or a group represented by —N(R₉)R₁₀(wherein R₉ and R₁₀ may be the same or different, and each represents ahydrogen atom, a lower alkyl group, a hydroxyalkyl group, a mono- ordi-lower alkylaminoalkyl group, a phenyl group, or a heterocyclic groupwhich may have a substituent)); R₄ represents a hydrogen atom, a loweralkyl group which may be substituted by a halogen atom, a lower alkoxylgroup, a halogen atom, a hydroxyalkyl group, an amino group, a nitrogroup, a mono- or di-lower alkylamino group, a loweralkylsulfonylaminocarbonyl group, a hydroxyaminocarbonyl group, abenzyloxyaminocarbonyl group, a tetrazolyl group, a 4-oxoxadiazolinylgroup, a group represented by the following formula:

 (wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R₁₁ represents ahydrogen atom, a lower alkyl group or a benzyl group); R₅ represents alower alkylsulfonylaminocarbonyl group, a hydroxyaminocarbonyl group, abenzyloxyaminocarbonyl group, a group represented by the followingformula:

 (wherein X represents an oxygen or sulfur atom), or a group representedby —Y—COOR₁₁ (wherein Y represents a single bond, alkylene, —O-alkylene,—S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R₁₁ represents ahydrogen atom, a lower alkyl group or a benzyl group); Ar represents abenzene or naphthalene ring, or an aromatic heterocyclic ring; and nrepresents an integer between 0 and 2 inclusive, wherein saidheterocyclic group independently is selected from 5 and 6 membered ringscontaining at least one heteroatom selected from the group consisting ofN, O and S; and wherein said substituent independently is selected fromone or two substituents selected from the group consisting of a loweralkyl group, a lower alkoxy group, a halogen atom, an amino group and anitro group.
 9. A pharmaceutical composition containing a compound asrecited in claim 1 and a pharmaceutically acceptable carrier.
 10. Apharmaceutical composition containing a compound as recited in claim 2and a pharmaceutically acceptable carrier.
 11. A pharmaceuticalcomposition containing a compound as recited in claim 3 and apharmaceutically acceptable carrier.
 12. A pharmaceutical compositioncontaining a compound as recited in claim 4 and a pharmaceuticallyacceptable carrier.
 13. A method of suppressing the secretion of gastricacid, in a mammalian subject in need thereof, which comprisesadministration of an effective amount of a compound as recited in claim1 to a mammal.
 14. The method of claim 13, wherein the mammal is ahuman.
 15. A method of treating a disease in which a gastrin receptorand/or cholecystokinin (CCK)-B receptor participates and selected fromthe group consisting of gastric ulcer, duodenal ulcer, gastritis, refluxesophagitis, and Zollinger-Ellison syndrome, comprising administrationof a compound as recited in claim 1 to a mammal, in an amount effectivefor binding to said gastrin receptor and/or said cholecystokinin (CCK)-Breceptor in said mammal.
 16. The method of claim 15, wherein the mammalis a human.